Vol. 28 No.

6 December 2004 Journal of Pain and Symptom Management 603 

Original Article 

Stability of Admixture Containing Morphine Sulfate, 

Bupivacaine Hydrochloride, and Clonidine Hydrochloride in an 
Implantable Infusion System 
Ashley M. Classen, DO, FAOCA, Gary H. Wimbish, PhD, DABFT, and Thomas C. Kupiec, PhD Trinity Pain Medicine 
Associates, PA (A.M.C.), Fort Worth, Texas; Forensic Toxicology Consultants, Inc. (G.H.W.), Milford, Texas; and Analytical 
Research Laboratories (T.C.K.), Oklahoma City, Oklahoma, USA 
Abstract Intrathecal infusion is often performed using drug combinations. This study was conducted to evaluate the 
stability of the admixture of morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride when used in 
an implantable pump under simulated clinical use conditions. SynchroMed implantable pumps were filled with an 
admixture and incubated at 37 C for a period of 90 days. Drug admixture stored in glass vials at 4 C and at 37 C 
served as controls. Samples which included pump reservoir and catheter delivered aliquots were collected every 30 
days and analyzed for drug concentrations using a stability-indicating HPLC method. All drugs contained in the 
admixture were stable and the original concentrations remained greater than 96%. Over 90 days, and with the 
pump at the simulated body temperature of 37 C, there were no evident heat catalyzed or device catalyzed reactions. 
J Pain Symptom Manage 2004;28:603–611. 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. 
All rights reserved. 
Key Words Implantable pump, stability, morphine sulfate, clonidine, bupivacaine 

Introduction 
Administration  of multiple analgesic drugs concurrently into the cerebrospinal fluid on a continuous basis from an 
implantable program- mable infusion system has become an accepted 
method  of  therapy  over  the  past  decade.1,2  This  practice  of  polyanalgesia  is  supported  by  only a few publications, 
but now is commonly em- ployed for the treatment of chronic pain.2,3 
Morphine  frequently  is  used  for  neuraxial  infusion,  but  may  produce  unwanted  side  ef-  fects,  particularly  at 
relatively high doses.4–7 
Address reprint requests to: Thomas C. Kupiec, PhD, Analytical Research Laboratories, 840 Research 
Patients receiving high intrathecal doses of morphine can develop a state of hyperalgesia Parkway, Suite 546, 
Oklahoma City, OK 73104, USA. 
and are at an increased risk of developing an Accepted 
for publication: April 1, 2004. 
inflammatory mass.8 
2004 U.S. Cancer Pain Relief Committee 0885-3924/04/$–see front matter Published by Elsevier Inc. All rights reserved. 
doi:10.1016/j.jpainsymman.2004.04.011 
 
604 Classen et al. 
Vol. 28 No. 6 December 2004 Bupivacaine is the drug most commonly used in combination with morphine for 
the treat- ment of neuropathic pain.9–15 The augmen- tation in pain relief by this combination is perhaps related to 
the additional effect of bupi- vacaine, which directly inhibits neuronal volt- age-gated sodium channels, as opposed 
to stimulating selected receptors. This combina- tion has been shown to reduce the need for escalating doses of 
morphine when used alone.16–18 
More recently, clonidine, an alpha2-adrener- gic receptor agonist, has been shown to be effective against 
neuropathic pain.19One mech- anism suggests that clonidine increases me- chanical threshold via activation of 
muscarinic m1 receptors in the spinal cord.20The combina- tion of clonidine and morphine via intrathecal 
administration has proven to be effective for chronic pain by producing a synergistic antino- ciceptive 
interaction.21–24 In addition, preclini- cal studies demonstrate decreased rates of inflammatory mass formation 
when clonidine is added to morphine intrathecal infusions.25 Further, clonidine in combination with bupiva- caine 
and morphine seems to fill a therapeutic deficit in the treatment of neuropathic cancer pain where other 
combinations have failed.26–29 The safe intrathecal delivery of morphine via implantable infusion pumps has 
become widely accepted for the treatment of intractable pain.4,5,30–33In addition, the safety of the admin- istration 
of bupivacaine via an implantable de- livery system has been investigated and shown to be stable and compatible 
with the delivery device and well tolerated when administered chronically in patients.34 However, the stability of 
the admixture of morphine, bupivacaine, and clonidine has been shown only in plastic reservoir bags at room 
temperature for the treatment of chronic pain syndromes.35 
This  study  investigates  the  stability  and  com-  patibility  of  these  agents  with  each  other  and  in  an  infusion pump 
system designed for in- trathecal delivery. 
Methods Drug Preparation 
The  drug  solutions  employed  in  this  study  were  prepared  by  Hartley  Medical  Center, Long Beach, California, to 
simulate drug combina- tion solutions used by physicians for intrathecal 
administration.  Stock  solutions  of  USP  mor-  phine  sulfate,  bupivacaine  hydrochloride, and clonidine hydrochloride 
were  prepared  in  ster- ile water for injection. The concentrations for the above solutions were morphine sulfate at 50 
mg/mL,  bupivacaine  hydrochloride  at  25  mg/mL,  and  clonidine  hydrochloride  at  2  mg/mL.  (Note:  These 
concentrations  are  rel-  atively  high,  but  clinically  relevant  to  maximize  any  potential  drug–drug  or  drug–device 
inter-  actions).  Each  solution  was  verified  by  our  vali-  dated  analytical  method  to  be  within  5.5%  of  the  stated 
concentrations prior to use. 
Equipment 
The  implantable  drug  delivery  system  evalu-  ated  was  the  18  mL  reservoir  SynchroMed  EL  pump  (Medtronic, 
Minneapolis,  MN,  USA)  with  a  silicone infusion catheter (model 8709, Medtronic). The pump allows programming 
by a noninvasive technique that also facilitated in- fusion rate changes during the study. 
Each  infusion  pump received from the manu- facturer contained sterile water and was emp- tied prior to use. Each 
pump  was  filled  with  the  admixture,  warmed  to  37  C  and  rinsed  with  10  mL  of  the  admixture  prior  to  filling. The 
incubator  system  used  for  this  study  was  a  Forma-  Scientific model 3932 which was maintained at 37 2 C to mimic 
in vivo temperatures. 
The analysis was performed using a Hewlett Packard (Wilmington, DE, USA), model 1050 high performance liquid 
chromatograph equipped with a diode array detector. The column employed was a Phenomenex Luna C 18(2) 
150mm 4.6 mm with a 5μ particle size. The pH of the solutions was obtained using a Corning model 350 pH/ion 
analyzer. The osmolality of the solutions was obtained using a Wescor model 5500 vapor pressure osmometer. 
Drug Solution Stability 
 Drug  solution  stability  was  determined  at  two  different  temperatures,  4  C  and  37  C  to  estab-  lish  the stability of 
the  drug  solution  stored  in  glass  and  protected  from  light.  These  serve  as  controls  for  the  primary  experiment.  A 
stan-  dard  containing  morphine  sulfate,  bupivacaine  hydrochloride,  and  clonidine  hydrochloride  was  assayed  to 
determine  their initial concentra- tions. This standard was transferred to two glass vials. One vial was protected from 
light and 
 
Vol. 28 No. 6 December 2004 Stability of Admixture in an Infusion System 605 stored at 4 2 C. The second vial 
was pro- tected from light, and stored at 37 2 C. Each solution was sampled at 0, 30, 60, and 90 days. Another 
identical admixture solution was sub- jected to a freeze-thaw cycle by placing it in the freezer for 4 hours, removing 
and then thawing for 4 hours. Upon completion of the thaw, the samples were reanalyzed and compared to the zero 
time-point analysis. This freeze-thaw cycle was performed because all samples were frozen and analyzed at one time 
at the end of the study. The temperature control samples al- lowed the evaluation of the stability of the drugs in 
solution independent of the infusion system. 
Drug Stability in Device 
In  order  to  compare  the  stability  of  the  ad-  mixture  in  the  pump  to  the  inherent  stability  of  the  admixture,  the 
control  admixture  solutions  (4  C  and  37  C)  of  morphine  sulfate,  bupiva-  caine  hydrochloride,  and  clonidine 
hydrochlo-  ride  were  assayed  in  parallel  with  the  pump  solution at designated intervals. Three Syn- chroMed pump 
systems  were  evaluated  at  37  C.  These  were  compared  against  identical  solu-  tions  protected  from  light  at  37 C to 
determine  any  device-induced  degradation.  A  third  identi-  cal  solution  protected  from  light, but at 4 C, was used to 
determine any heat-related degradation. 
The relevant drug infusion system consists of a pump-reservoir and catheter. Three of these infusion systems were 
utilized and sampled at 0, 30, 60, and 90 days. One-milliliter samples were taken from each control solution and two 
1-mL samples were collected from each infu- sion system at the designated time interval. The first sample was taken 
directly from the pump reservoir via the septum port. The second was taken through the catheter by setting the pump 
at the maximum flow rate to produce 1 mL and then shut off at the completion of each collection. This procedure 
also assessed the de- livery function and accuracy of the device after admixture exposure. The samples were col- 
lected into pre-labeled glass vials. The time zero solution for each was analyzed at the beginning of the study and 
then stored in the freezer at 20 C to be thawed and re-assayed at the end of the study. Freezing had no effect on the 
assay results as demonstrated by the freeze-thaw study. The remaining samples were collected at the designated 
times, 30, 60, and 90 days, and 
stored  in  the  freezer  at  20  C  until  the  end  of  the  study.  All samples were then thawed and allowed to come to room 
temperature and as- sayed as a batch. 
Physical Stability of Solution 
The  physical  stability  of each admixture was evaluated by visual inspection for color and par- ticulate matter. The 
pH  of  each  solution  was  measured  at  each  time  interval  and  osmolality  was  assessed  only  for  the  time-zero  and 
90-day samples. 
Analytical Methods 
An  HPLC  stability-indicating  method  was  de-  veloped  and  validated  for  morphine  sulfate,  bupivacaine 
hydrochloride,  and  clonidine  hy-  drochloride  quantitation.  USP  guidelines,  Vali-  dation  of  Compendial  Methods 
(Chapter  1225),  Chromatography  (Chapter  621),  FDA,  and  ICH  guidelines  were followed in the valida- tion of this 
stability  indicating  method.  Separate  source  analytical  standards  were  used  in  the  validation  of  the  analytical 
method.  A  gradient  elution  method  allowed  resolution  of  the  above  drugs  using  a  single  method.  The  established 
analytical  range  was  from  25–125%  of  the  target  value  for  each  drug.  The  mobile  phase  was  com-  posed  of  two 
solutions. Solution A was 39 mM K 
2 
HPO 
4 
at  pH  9.  Solution  B  was  HPLC-grade  methanol  (Pharmco  Inc.,  lot  no.  HM020502).  The  flow rate was at 
1.0  mL/min  with  an  injec-  tion  volume  of  20μL.  The  detection  wavelength  was  210  nm.  The total run time was 13 
minutes per sample. 
Results Drug Solution Stability 
When  combined,  morphine  sulfate,  bupiva-  caine  hydrochloride, and clonidine hydrochlo- ride did not change by 
more  than  5%  when  compared  to  their  respective  concentrations  at  time  zero.  After  90  days  at  4  C,  the mean con- 
centration  of  morphine  sulfate,  bupivacaine  hy-  drochloride  and  clonidine hydrochloride were 100.7%, 100.7% and 
98.0%  respectively,  com-  pared  to  the  concentration  at  time  zero.  The  4  C  results  are  graphically  represented  in 
Figure 1. 
At 90 days and 37 C, morphine sulfate re- tained 100.0% of its original concentration 
 
606 Vol. 28 No. 6 December 2004 Classen et al. 
Fig. 1. Morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride concentrations in the samples stored at 4 C 
over a 90-day period. 
from  time  zero.  For  the  same  conditions,  bupi-  vacaine  hydrochloride  maintained  104.2%  of  its  original 
concentration  and  clonidine  hydro-  chloride  maintained  99.0%  of  its  original  con-  centration  with  respect  to  time 
zero. The 37 C results are graphically represented in Figure 2. 
Drug Stability in Device 
After  90  days  of  incubation  at  simulated  body  temperature  (37  C)  within  the  implantable  pumps,  the 
concentrations of the drugs of inter- est did not deviate by more than 4.4% from the time zero concentration. 
Morphine  sulfate  showed  reservoir  concen-  tration  values  of  49.60  mg/mL,  49.60  mg/mL,  49.21  mg/mL,  and 
49.53  mg/mL  for  the  0,  30,  60,  and  90-day intervals, respectively. The 90-day reservoir concentrations of morphine 
sulfate  did  not  deviate  more  than  0.8%  when  com-  pared  to  initial  reservoir  concentrations  at  time  zero.  Catheter 
concentrations of mor- phine sulfate were 48.76 mg/mL, 50.04 mg/mL, 
49.57 mg/mL, and 49.31 mg/mL for day 0, 30, 60, and 90, respectively. The 90-day catheter concentrations of 
morphine sulfate did not de- viate more than 2.2% when compared to initial concentrations at time zero. Morphine 
sulfate results are graphically represented in Figure 3. Bupivacaine hydrochloride had reservoir concentration values 
of 25.33 mg/mL, 25.59 mg/mL, 25.56 mg/mL, and 25.39 mg/mL for the 0, 30, 60, and 90-day intervals, 
respectively. The 90-day reservoir concentration of bupiva- caine hydrochloride did not deviate more than 
1%whencomparedtoitsinitialconcentrationat time zero. Catheter bupivacaine hydrochloride concentration values 
were 24.65 mg/mL, 25.72 mg/mL, 25.73 mg/mL, and 25.68 mg/mL, for days 0, 30, 60 and 90, respectively. The 
90-day catheter concentration of bupivacaine hydro- chloride did not deviate more than 4.4% when compared to its 
initial concentration at time zero. Bupivacaine hydrochloride results are graphically represented in Figure 4. 
Fig. 2. Morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride concentrations in the samples stored at 37 C 
over a 90-day period. 
 
Vol. 28 No. 6 December 2004 607 Stability of Admixture in an Infusion System 
Fig.  3.  Morphine  sulfate  reservoir  and  catheter  concentrations  vs.  time.  Reservoir concentrations are indicated by the bold black 
line  for  0,  30,  60,  and  90-day  time  intervals.  Catheter  concentrations  are  indicated  by  the  black  dotted  line  for  the  same  time 
points.  Bold  black  lines  indicate  10%  of  the initial reservoir concentration. Black dotted lines indicate 10% of the initial catheter 
concentration. 
Clonidine  hydrochloride  showed  reservoir  concentration  values  of  1.90  mg/mL,  1.88  mg/  mL,  1.90  mg/mL,  and 
1.83  mg/mL  for  the  0,  30,  60,  and  90-day  intervals,  respectively.  At  90  days,  the  reservoir  concentration  of  cloni- 
dine  hydrochloride  did  not  deviate  more  than  3.2%  when  compared  to  reservoir  concentra-  tions  at  time  zero. 
Catheter  concentrations  of  clonidine  hydrochloride  were  1.83  mg/mL,  1.94  mg/mL,  1.88  mg/mL,  and  1.86 mg/mL 
for  days  0,  30,  60,  and  90,  respectively.  At  90  days,  the  catheter  concentration  of clonidine hydro- chloride did not 
deviate  more  than  6.6%  when  compared  to  catheter concentrations at time zero. Clonidine hydrochloride results are 
graphically represented in Figure 5. 
Table 1 is a comparison of the above data versus the data collected for the 37 C control group as seen in Figure 2. 
Physical Stability of Solution 
Table 2 lists the results of the pH of the solu- tions that were obtained for each sample at each time point. 
Table  3  lists  the  observations  for  color  and  particulate  matter  made  for  the  solutions  col-  lected  from  the pumps 
with respect to the source and time. 
In  addition  to  these  tests  and  observations,  the  osmolality  for  the  beginning  solution  and a sample from the 37 C 
stored  for  90  days  were analyzed. The initial osmolality was 273 mmol/ Kg and the osmolality of the 90-day sample 
was  270  mmol/Kg.  The  results  for  the  samples  removed  from  the  reservoir  of  the  infusion  pump  were  100.1%, 
100.2%,  and  96.8%  relative  to  time  zero  for  morphine  sulfate,  bupiva-  caine  hydrochloride,  and  clonidine 
hydrochlo- ride, respectively. The results for the samples 
Fig.  4.  Bupivacaine  hydrochloride  reservoir  and  catheter  concentrations  vs.  time.  Reservoir  concentrations  are  indicated  by  the 
bold black line for 0, 30, 60, and 90-day time intervals. Catheter concentrations are indicated by the black dotted line for the same 
time  points.  Bold  black  lines  indicate  10%  of  the  initial  reservoir  concentration.  Black  dotted  lines  indicate  10%  of  the  initial 
catheter concentration. 
 
608 Vol. 28 No. 6 December 2004 Classen et al. 
Fig.  5.  Clonidine  hydrochloride  reservoir and catheter concentrations vs. time. Reservoir concentrations are indicated by the bold 
black line for 0, 30, 60, and 90-day time intervals. Catheter concentrations are indicated by the black dotted line for the same time 
points.  Bold  black  lines  indicate  10%  of  the initial reservoir concentration. Black dotted lines indicate 10% of the initial catheter 
concentration. 
removed from the catheter of the infusion 
points had less than 1 pH unit change. These pump were 
100.1%, 100.2%, and 96.8% relative 
variations had little or no effect on the concen- to time 
zero for morphine sulfate, bupiva- 
trations of the drugs in the solutions. caine 
hydrochloride, and clonidine hydrochlo- 
A change in the color of the solutions from ride, 
respectively. The results of all the samples 
colorless to light yellow was observed between were 
within 5% of the results of time zero. 
the 30- and 60-day time points. This has been Figures 1 
and 2 show that the control samples 
observed in injectable solutions of morphine were stable 
over the 90-day time period. Fig- 
sulfate and identified as pseudomorphine.36 ures 3 and 4 
show that the infusion pump sam- 
This color change did not affect the stability of ples were 
stable over the 90-day period. The 
the solution. The examination for particulate results 
indicate no degradation occurred in any 
matter was performed to determine if any of of the 
samples. This conclusion also extends to 
the components of the matrix were precipitat- the 
stability of the solution stored in the infu- 
ing during storage of the solutions. No particu- sion 
pump. This indicates that no degradation 
late matter was noted over the 90-day period. is apparent 
over the 90 day time period and 
Osmolality tests were performed at time zero thus had 
no effect on the analysis of the sample. 
and 90 days after being stored at 37 C. The slight Table 2 
lists the results of the pH of the sam- 
difference of the results between these samples ples 
collected at each time point. The 37 C con- 
 is not clinically significant. The calculations for trol 
samples and catheter samples showed the 
the results were based on the data obtained by only 
significant changes over time. The 37 C 
analysis of the samples using the validated control 
samples had a change of 1 to 3.6 pH 
HPLC method. Reference standards of each units over 
the 90-day time period whereas the 
analyte were prepared and the peak areas of 37 C 
catheter samples rose from 3.8 to 5.1 pH 
these reference standards were compared units between 
0 and 30 days. The other time 
against the peak areas of the study samples. This 
Table 1 Results of Catheter and Reservoir Concentrations for Morphine Sulfate, Bupivacaine HCl, Clonidine HCl, and 37 
C Control Samples at 0, 30, 60, and 90-Day Intervals 
Bupivacaine HCl Clonidine HCl Morphine Sulfate 
Day Reservoir Catheter 37 C S.D. Reservoir Catheter 37 C S.D. Reservoir Catheter 37 C S.D. 
0  25.33  24.65  25.64  0.51  1.90  1.83  1.97  0.07 49.60 48.76 50.30 0.77 30 25.59 25.72 26.16 0.30 1.88 1.94 2.01 0.07 49.60 50.04 
50.59  0.50  60  25.56  25.73  26.46  0.48  1.90  1.88 1.93 0.03 49.21 49.57 50.14 0.47 90 25.39 25.68 26.71 0.69 1.83 1.86 1.95 0.06 
49.53 49.31 50.31 0.53 
 
Vol. 28 No. 6 December 2004 Stability of Admixture in an Infusion System 
609 Table 2 Results of pH Determinations for Different Sample Groups 4 C, 37 C, 37 C Reservoir, and 
37 C Catheter, at 0, 30, 60 and 90 Days 
pH Sample Groups 
Time 4 C 37 C 37 C 37 C Period Control Control Reservoir Catheter 
0 4.6 4.6 4.8 3.8 30 5.0 5.2 5.2 5.1 60 3.9 5.1 4.7 4.8 90 3.6 4.7 4.5 4.6 
Each result is the mean of 3 pH determinations. 
comparison  yielded  the  concentration  of  the  analytes  in  the  study  solutions.  Overall  stability  of  the  solutions  was 
established  by  determining  the  percent difference between the results from 90 days to the results obtained from time 
zero.  In  order  for  the  solutions  to  be  considered  stable,  there  must  not  be  a  change  in  the  con-  centration  of  any 
analyte  greater  than  10%.  Based  on  these  calculations  and  this  criterion  all  solutions remained stable for at least 90 
days. 

Discussion 
Although  management  of  intractable  pain  using  long-term  intrathecal  analgesic  adminis-  tration  by  implantable 
infusion  systems  has  become  accepted clinical practice, this method presents unique challenges regarding the stabil- 
ity  of  the  pharmaceutical  agent(s)  delivered.  Two  major  challenges  include:  1)  the  require-  ment  to  use 
preservative-free  formulations  to  avoidneurotoxicity,and2)prolongedstorageof  the  formulation  at  elevated 
temperature  (i.e.,  body  temperature)  within  the  reservoir  of  the  delivery  system.  Adjunctive  analgesics  such  as 
bupivacaine and clonidine frequently are added 
Table 3 Results for Color and Particulate Matter of Reservoir and Catheter Admixture Samples at 0, 30, 60, and 90-Day 
Intervals 
Day Sample Color Particulate 
Initial  Initial  Colorless  No  Particulate  0  Reservoir  Colorless  No  Particulate  30  Reservoir  Colorless  No  Particulate 60 Reservoir 
Light  Yellow  No  Particulate 90 Reservoir Light Yellow No Particulate 0 Catheter Colorless No Particulate 30 Catheter Colorless 
No Particulate 60 Catheter Light Yellow No Particulate 90 Catheter Light Yellow No Particulate 
to  the  infusate  because  of  inadequate  efficacy  or  intolerable  side  effects  associated  with  opioid  monotherapy. 
Moreover,  the  use  of  polyanalge-  sia  may limit morphine exposure and thus reduce the risks of opioid tolerance and 
cathe-  ter-tip  inflammatory  mass  formation.8,38  When  using  drug  combinations,  the  chemical  and  physical 
compatibility of the individual drug components of the admixture also must be care- fully assessed. 
Long-term  stability  and  compatibility  of  mor-  phine-clonidine  admixtures  (20  mg  morphine  sulfate  0.05  mg 
clonidine  hydrochloride  per  mL  and  2.0  mg  morphine  1.84  mg  clonidine  per  mL)  in  the  SynchroMed  system,  the 
same  system  as  employed  in  our  studies,  has  been previously reported.37 These authors reported that morphine and 
clonidine  concentrations  remained  at  94%  of  initial  concentration after storage in the infusion system at 37 C for 90 
days.  The  stability  of  bupivacaine  hydrochlo-  ride  (7.5  mg/mL)  in  the  SynchroMed  infusion  system  also  has  been 
reported.34  Bupivacaine  concentrations  remained  greater  than  96%  of  the  initial  concentration  when  stored  for  90 
days  at 37 C. Moreover, the compatibility of the individual analgesics, namely morphine, clonidine, and bupivacaine 
with the Syn- chroMed delivery system also has been confirmed.34,37 
The  stability  of  admixtures  containing  mor-  phine  (6.66  mg/mL),  bupivacaine  (3  mg/mL),  and  clonidine  (30 
μg/mL)  has  been  previously  reported.35  These  solutions  were  preservative-  free, stored for 90 days, protected from 
light,  and  analyzed  using  HPLC.  Although  the  chemi-  cal  and  physical  stability  of  these  agents  com-  bined  in 
aqueous  solution  was  confirmed,  there  are  several  important  distinctions  between  the  previous  study  and  the  one 
reported  here.  The  previous  study  used  morphine  hydrochlo-  ride  (commonly  available  in  Europe),  rather  than 
morphine  sulfate  (the  only  morphine  salt  available  in  the  U.S.).  As  both  clonidine  and  bupivacaine  are  also 
hydrochloride  salts,  the  chance of unfavorable interactions is less than with the sulfate form of morphine. Moreover, 
relatively  low  concentrations  of  each  analgesic  were  used  and  most  importantly,  the  drug  solu-  tion  was  stored  in 
plastic ambulatory pump cas- settes at room temperature. 
The study presented herein is significant in several ways. It represents the first study that 
 
610 Classen et al. Vol. 28 No. 6 December 2004 specifically addresses the long-term stability of a commonly used 
analgesic trimixture. Further- more, it evaluates the stability of each com- ponent at the highest clinically relevant 
concentration (morphine sulfate, 50 mg/mL; bupivacaine hydrochloride, 25 mg/mL; and clonidine hydrochloride, 2 
mg/mL) to ensure that the potential of degradation processes in- volving intermolecular interactions in solu- tion are 
maximized (i.e., worst-case scenario). It should be appreciated that in actual clinical practice, it is unlikely that each 
analgesic of a three-drug combination would be present at maximal concentration. On the other hand, high 
concentrations of at least the primary opioid analgesic but often the adjuvant analge- sics as well are used in 
implantable pumps in order to maintain reasonable refill intervals. Because dosing is a function of concentration and 
infusion rate, high concentration infusates are able to maintain effective analgesia while minimizing the volume of 
infusate expended. However, because high concentration mor- phine sulfate may be associated with inflamma- tory 
mass formation, using adjuvants such as bupivacaine and clonidine allow opioid expo- sure (dose and concentration) 
to be reduced without sacrificing adequate pain control. The results of this study provide assurance that 
combinations of these three commonly used analgesics at clinically relevant maximal con- centrations maintain 
appropriate chemical and physical stability when stored in an implantable SynchroMed infusion system under 
simulated clinical conditions. 

Conclusion 
The  admixture  containing  morphine  sulfate,  bupivacaine  hydrochloride,  and  clonidine  hy-  drochloride  is  stable 
when  stored  at  4  C  and  37  C  in  vitro  for  90  days.  In  addition,  it  is  stable  at  37  C  in  the  SynchroMed  EL  infusion 
pump  for  90  days  and  no  heat-  or  device-catalyzed  reactions  were  evident.  Accurate  pump  delivery  function  was 
maintained  throughout  the  study.  The  study  thereby  indicates  that  these  drugs  are  stable  with  the  SynchroMed  EL 
infu- sion pump. 

Acknowledgments 
Funding for this study was provided by Med- tronic Neurological, Columbia Heights, Minne- sota, USA. 

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