1042

Journal of Pain and Symptom Management

Vol. 22 No. 6 December 2001

Original Article

Stability and Compatibility of Hydromorphone

Hydrochloride in an Implantable
Infusion System
Keith R. Hildebrand, DVM, PhD, Dennis E. Elsberry, DVM, PhD,
and Valerie C. Anderson, PhD
Medtronic, Inc. (K.R.H., D.E.E.), Minneapolis, Minnesota, and Department of Neurological Surgery
(V.C.A), Oregon Health Sciences University, Portland, Oregon, USA

Abstract
With the exception of morphine, hydromorphone is the most commonly used intrathecal opioid
for the treatment of intractable pain. The purpose of this study was to evaluate the stability
and compatibility of hydromorphone in the implantable infusion system that is most commonly
used in these patients. Hydromorphone solution was incubated at 37C in infusion system
reservoirs and with individual materials which comprise the fluid pathway of the infusion
system. Stability was analyzed using high performance liquid chromatography; mechanical
integrity of device materials was evaluated after drug exposure. After 4 months of exposure to
device materials or intact devices, hydromorphone concentration remained greater than 95%
of starting material. All device materials retained acceptable mechanical performance. These
results demonstrate that hydromorphone is stable at physiological temperatures for at least 4
months in an implantable infusion system and that current clinical practice of refilling the
pump every 3 months is appropriate. J Pain Symptom Manage 2001;22:1042
1047 U.S. Cancer Pain Relief Committee, 2001.
Key Words
Hydromorphone, opioid, stability, compatibility, intrathecal, implantable pump

Introduction
Intrathecal delivery of opioids using implantable infusion systems has become an accepted
method for long-term management of severe
malignant pain.14 The intrathecal route of delivery significantly increases the therapeutic index of this class of analgesics as compared to

Address reprint requests to: Keith Hildebrand, DVM,

PhD, Medtronic, Inc., 710 Medtronic Parkway, Minneapolis, MN 55432-5604, USA.
Accepted for publication: March 9, 2001.
U.S. Cancer Pain Relief Committee, 2001
Published by Elsevier, New York, New York

oral or other parenteral routes of administration.5 In addition, implantable infusion technology allows much lower doses of medication to
be infused chronically with reduced risk of infection and without the patient inconvenience
associated with ambulatory infusion systems.
Opioids are the most commonly used agents
for intrathecal management of pain. Morphine
sulfate is the most frequently used and only approved agent for long-term intrathecal infusion. Another opioid that is commonly used,
though, is hydromorphone hydrochloride.2,3,6,7
Hydromorphone (HM) is a semisynthetic hydrogenated ketone of morphine (Figure 1)
that is approximately five times more analgesic
0885-3924/01/$see front matter
PII S0885-3924(01)00364-5

Vol. 22 No. 6 December 2001

Hydromorphone Stability in Implantable Pumps

than morphine.810. The duration of action (4

5 hours) and plasma half life (23 hours) of
HM following parenteral administration are
comparable to morphine.11 Moreover, the opioid-receptor selectivity of HM is similar to morphine. Both are considered high-affinity, selective mu-receptor agonists.
The stability of HM and its compatibility with
implantable infusion systems have not been confirmed. Because of the low intrathecal doses
needed to manage chronic pain and the fixed volume of the infusion pump, refill is generally required only 3 to 5 times per year. Therefore, it is
important that the preservative-free drug solution
remain stable at body temperature for prolonged
intervals. Drugs that degrade significantly or form
precipitates within the infusion reservoir are not
suitable for prolonged intrathecal use. In addition, although materials which comprise the fluid
pathway of the infusion systems are selected because of their mechanical and chemical robustness, unless the specific pump and catheter system is tested with the drug solution of interest, it
cannot be assured that material degradation or
system failure will not occur.
The stability and compatibility of morphine
sulfate (Infumorph) with a commonly used
implantable infusion system (SynchroMed,
Minneapolis, MN) has been previously demonstrated (Medtronic data on file). The purpose
of this study is to investigate the stability of HM
in this delivery system and the compatibility of
drug with device materials.

1043

Methods
The stability of HM (Dilaudid, Mount Olive,
NJ) was evaluated in vitro using two different yet
complementary methods. In the first method
(drugmaterial stability), the effect of materials
present along the drug-device interface on HM
stability was evaluated. In the second method
(drugdevice stability), stability was evaluated using an intact pump-catheter system. As tested, the
formulation contained HM at a concentration of 2
(Dilaudid, Wilmington, DE) or 10 mg/mL (Dilaudid-HP)in a 0.2% sodium citrate buffer solution,
pH 4.1.

Equipment and Conditions

Stability analyses were performed using high
performance liquid chromatography (HPLC).
A Hewlett Packard (Palo Alto, CA) 1090A liquid chromatograph with a diode array detector
was used. The stationary phase was a Dupont 5
micron, C18 reverse-phase column (150  4.6
mm); the mobile phase was a 59/49/1 (V/V/
V) mixture of 5 mM heptane sulfonic acid/
methanol/acetic acid. The detector was set at
280 nm. Flow rate of the mobile phase was constant at 1 ml/min; sample injection volume was
10 l. This method displayed good linearity
(correlation coefficient 0.999) and precision
(coefficient of variation 1.98%) with 3% accuracy during duplicate injections. The limit of
detection was approximately 10 g/ml.

DrugMaterial Stability
HM (10 mg/mL) was exposed to each of 6
different materials that comprise the infusion
pathway of the delivery system for 16 weeks.
Samples of each material were incubated with
HM in glass ampules sealed to prevent evaporation and maintained at 37C with continuous
agitation. HM incubated in the absence of any
device material served as a control. Fluid samples were collected after 1, 2, 4, 8, and 16
weeks. HM concentration was determined in
each and expressed as a percentage of the concentration of HM contained in a fresh solution
of the same lot.

DrugDevice Stability
Fig. 1. Chemical structures of morphine and hydromorphone. Hydromorphone differs structurally
from morphine by the substitution of an oxygen for
the 6-hydroxyl group and hydrogenation of the 78
double bond.

Three SynchroMed infusion systems were

tested. Attached to each pump was a silicone
catheter (Model 8703, Medtronic, Inc.). The
reservoirs of the pumps (18 ml) were filled
with HM (2 mg/ml). The infusion systems

1044

Hildebrand et al.

Vol. 22 No. 6 December 2001

were maintained at 37C to simulate implant

conditions and programmed to deliver at a
constant rate of 90 l/day. HM aliquots were
collected every two weeks over 16 weeks from
two different locations: the reservoir of the
pump and the exit port of the catheter. No refills were made to the pump reservoirs during
this time. Control solution was maintained in a
sealed vial at room temperature and protected
from light. Concentrations in the reservoir and
at the catheter tip were expressed as percentages of the control concentration.

DrugDevice Compatibility
To evaluate effects of prolonged HM exposure on materials that comprise the fluid pathway of the infusion system, the following tests
were conducted. Each material was immersed
in HM (10 mg/ml) contained in sealed glass
ampules (5 pieces of material per ampule).
Ampules were maintained at 37C with constant agitation for 16 weeks. Material samples
were collected at 1, 2, 4, 8, and 16 weeks after
immersion. Tensile strength and percent elongation at break point of elastomers were assessed using a pull-tester machine.12 Flow rate
(water at 10 psi) through the in-line filters was
evaluated. Hardness of the septum through
which drug solution is added to the reservoir
was evaluated to ensure proper sealing following needle puncture.12

Fig. 2. Concentrations of material-exposed hydromorphone over time. Each material of the delivery
system was incubated with hydromorphone for 16
weeks at 37C. The concentration was expressed as a
percentage of drug contained in fresh solution
(control). Open squares, filled squares  pump
elastomers, open triangles  catheter material,
filled triangles  refill septum, open circles  titanium, filled circles  pump filter, open diamonds 
control.

DrugDevice Stability
Samples collected from 3 SynchroMed infusion systems maintained at 37C are shown in
Figure 3. When expressed as percent concentrations of control, all 16-week samples collected from either the pump reservoir or the
catheter exit port had mean HM concentrations  95%. No individual sample exhibited a
concentration  92.5% of control. HPLC chro-

Results
DrugMaterial Stability
After 16 weeks of incubation with each material that comprises the fluid pathway of the infusion system, none of the HM samples analyzed demonstrated significant loss of drug
(Figure 2). HM concentration was  3% of
that measured in fresh solution. As shown, control solution unexposed to device materials
demonstrated HM concentrations of 99.8%
and 98.5% at 8 and 16 weeks, respectively. In
addition, none of the material-exposed HM samples demonstrated a consistent time-dependent
decrease in concentration. The reason for the
slight decrease in concentration observed after
exposure to one type of elastomer (filled circles) is not clear but may be due to adsorption
to the material. At 16 weeks, material-exposed
samples and the control solution pH was 4.2
(compared to 4.1 in fresh solution).

Fig. 3. Concentrations of device-exposed hydromorphone over time. Complete delivery systems (N  3,

pumps plus intrathecal catheters) were tested. Concentration of samples collected from the pump reservoir (open circles) or from the exit port of the
catheter (filled circles) was expressed as a percent of
control. Plotted values represent the mean  SD.

Vol. 22 No. 6 December 2001

Hydromorphone Stability in Implantable Pumps

1045

Table 1
Mechanical Performance of Device Materials Before and After 16-Week Hydromorphone Exposurea
Tensile Strengthb (psi)
Material
Elastomer Ae
Elastomer B
Catheter
Pump filter
Refill septum

% Elongationc

Flow rate (ml/30 sec)

Hardness (durometer)

Before

After

SDd

Before

After

SD

Before

After

SD

Before

After

SD

1586
1420
589

1600
1330
570

36
60
26

771
870
669

729
825
657

21
30
23

1.85

1.85

0.08

49.2

48.3

1.3

concentration  10 mg/ml, T  37C.

force measured at breaking point.
cMean percent elongation at breaking point versus unstretched condition.
dStandard deviation from 5 samples per material.
eElastomers A and B are components of the internal pump mechanism.
aHydromorphone
bMean

matograms of device-exposed HM revealed no

additional peaks. In contrast, HM degradation
peaks were identified after exposure to electric
current. In addition, HM samples did not demonstrate a time-dependent decrease in concentration.

DrugDevice Compatibility
All device materials exposed to HM solutions
for 16 weeks demonstrated acceptable mechanical performance. Tensile strength and
elongation of the 3 different elastomers displayed no significant changes from initiation
to completion of the experiment (Table 1).
Throughout the test period, the elastomers exhibited physical properties that were within the
qualification specification of each material required for use in the delivery system.12 Hardness of the access septum and flow rate of the
pump filter were likewise unaffected by
chronic HM exposure (Table 1).

Discussion
Long-term intrathecal opioid administration
by means of implantable infusion systems presents several unique challenges in terms of stability of the pharmaceutical agent being 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.
As noted previously, long-term stability of
morphine sulfate in the SynchroMed system
has been previously established (Medtronic
data on file). Aqueous preservative-free mor-

phine at room temperature has been reported

to be stable for 12 days,13 6 weeks,14 3
months,15,16 and 18 months.17 Morphine has
also been reported to be stable for 2 months at
32C18 and 1 month at 37C.19 Long-term stability of morphine and similarity in chemical
structure between morphine and HM (Figure
1) suggest similar stability properties of aqueous HM solutions.
This is the first report that specifically addresses the stability and compatibility of HM
with an implantable delivery system. Coombs
and colleagues suggested that HM is stable at
body temperature when chronically administered via an implantable infusion pump.6 Unfortunately, these data and the specifics of
their methodology were not reported. Admixtures of HM with fluorouracil (an antineoplastic) and with ondansetron (an antiemetic)
have been demonstrated to be stable at 32C
for at least 7 days and at least 31 days at room
temperature.20,21 Admixtures of HM and bupivacaine have been shown to be stable at 24C for
72 hours in polyvinyl-chloride containers.22
Results of the present study indicate that
commercially available preservative-free HM hydrochloride solution is stable within the SynchroMed infusion system for at least 4 months.
Three to four months is a typical interval between pump reservoir refills (outpatient appointments) for implantable infusion pumps
used for treatment of chronic pain. Drug-material testing using the compositional materials of
the delivery system also corroborate the stability
of the HM formulation. All HM solutions evaluated after 16-week exposure to either infusion
systems or infusion system materials exhibited
concentrations  95% of control solutions.

1046

Hildebrand et al.

The HPLC-UV detection method used to

quantify HM in device- or material-exposed
samples proved to be sensitive, accurate, and
precise. HPLC has been the method of choice
for quantifying opioids in a variety of matrices
with methods of detection including diode array,23 fluorescence,24 electrochemical,25,26 and
mass spectrometry.27,28 Another proven method
of opioid analysis is gas chromatography with
mass spectrometry detection.29,30 Although
mass spectrometry is more expensive than
other traditional methods of detection, when
combined with either liquid or gas chromatography, it can significantly lower the limit of
quantification, an advantage which is often desired with biological matrices.
This study also demonstrates the compatibility of device materials with HM after chronic
incubation at temperatures representative of
clinical use. All materials that comprise the
fluid pathway of the delivery system demonstrated appropriate mechanical integrity after
16 weeks. Moreover, the infusion system maintained appropriate function throughout the
course of the in vitro testing. Clinical practice
demands longevity of implantable infusion systems for at least 5 years. The 4-month HM-device
compatibility data and the clinical history of
the SynchroMed infusion system to deliver
morphine, a chemically similar opioid, chronically in patients suggest that long-term patient
management with HM is reasonable.
In conclusion, these results demonstrate
that a commercially available formulation of
HM has acceptable stability and material compatibility when tested over a 16-week period.
Based on these data, the current clinical practice of refilling the reservoir of the pump every
three months is acceptable from a stability
compatibility perspective.

Acknowledgments
The authors would like to acknowledge Harris
Ratnayake for analytical support of this research.

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