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Compatibility of tramadol parentral injection with
selected drugs and solutions
2
1. Norah O. Abanmy Msc.
Master degree in clinical pharmacy
Lecturer & clinical pharmacist
College of pharmacy- King Saud University, Riyadh, Saudi Arabia
nabanmy@ksu.edu.sa
2. Iman Y. Zaghloul
Associate professor of pharmacy
Associate professor in department of clinical pharmacy
College of pharmacy- King Saud University, Riyadh, Saudi Arabia
Zaghloul@ksu.edu.sa
Reprints and correspondence: Iman Zaghloul
P.O. Box , 22452, Riyadh 11495
Tel. 00966-1-4772546
Fax. 00966-1-4772546
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Compatibility of tramadol parentral injection with
selected drugs and solutions
Abstract:
Purpose: The compatibility of tramadol injection with selected drugs and commonly infused solutions
was studied using different methods.
Methods: Unasyn, Ranitidine, clindamycin, Ondansetron, Acyclovir were mixed separately in
minibags containing 0.9% sodium chloride injection, 5% dextrose injection, 20% mannetol, ringer, and
compound sodium lactate; admixtures were stored for up to 48 hours at either 4 oc or 25oc. Tramadol, at
a concentration of 0.4 mg/ml, was also combined separately with each of the other drugs and solutions
and stored under the same conditions. In addition, adsorption of tramadol to intravenous infusion set
was studied in polyvinyl cellulose tubing. The infusion set was completely filled with preassayed
solution of tramadol in 0.9% sodium chloride and samples were drawn for up to 6 hours. Also, the
adsorption of tramadol to polyvinyl cellulose syringes was determined by allowing the tramadol
injection solution to stand for 24 hours. Tramadol concentration were measured using a specific,
accurate and a simple stability indicating high performance liquid chromatography assay (HPLC).All
admixtures were also examined visually. Stability was defined as retention of at least 90% of the
original drug concentration with no visual evidence of incompatibility.
Results: With no exception, tramadol concentration in all different intravenous solutions was stable for
48 hours. When tramadol was combined with unasyn, ranitidine, and ondansetron drug concentration
was stable for 48 hours in sodium chloride and dextrose. A precipitate was formed immediately
whenever tramadol was mixed with clindamycin and acyclovir.Tramadol adsorption to intravenous sets
and syringes was minimal.
Conclusion: Tramadol injection was compatible with unasyn, ranitidine, and Ondansetron.But should
not be mixed or administered simultaneously through the same line with clindamycin and acyclovir
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Introduction:
Tramadol hydrochloride (( ± trans-2-(dimethyleaminomethyl)-1-(m-methoxy phenyl)cyclohexanol hydrochloride;tramadol) is a centrallyacting synthetic analgesic, with a
dual mechanism of action.1,2 Tramadol and its metabolite, O-desmethyl (M1), bind to
opioid receptors. The metabolite, M1, has a 200-fold higher affinity to the opioid
receptors. Tramadole has also been shown to inhibit the uptake of norepinephrine and
serotonin, suggesting that its antinociception activity is mediated by both opioid and
nonopioid mechanisms.1,3 In patients with diabetic neuropathy, oral tramadol
maintained low pain scores and high pain relief scores.4 Tramadol produced effective
analgesia with minimal side effects in cancer patients with chronic pain.5 Tramadol is
now a useful alternative in patient controlled epidural analgesia (PCEA) when patients
are not candidates for combined spinal-epidural analgesia (CSEA) for labor.6 There
are some clinical situations in which combination therapy with tramadol and another
drugs may be necessary such as those patients with postoperative pain needing pain
killer and antibiotic therapy or when tramadol used as adjunct to analgesicsupplemented anesthesia for a variety of surgical procedures. In addition patients
receiving tramadol are likely to receive other intravenous medications concurrently.
There may be a need for tramadol and other agents to be administered through the
same intravenous line.The objective of this study was to investigate the combatibility
of tramadol injection with different infusion solution such as 0.9% sodium chloride,
5% dextrose , 20% mannetol, ringer, and compound sodium lactate at room
temperature and under refrigeration and in admixtures of unasyn, ranitidine,
clindamycin, ondansetron, and acyclovir.
5
Methods:
Material:
Tramadol intravenous injection was added to the following infusion solution: 0.9%
sodium chloridea, 5% dextroseb, 20% mannitolc, ringerd, and compound sodium
lactatee. Also stability of tramadol has been studied with different drugs such as
unasynf ( ampicillin sodium 1000mg\ sulbactam sodium 500mg), ranitidineg,
clindamycinh, ondansetroni, and acyclovirj. The physical and chemical stability of
tramadol in the different infusion solution and in admixture with the above drugs were
studied in addition to its adsorption to both syringes and intravenous infusion sets (
venosetk and accusetl). Tramadol at concentration of 0.4 mg/ml was used. The study
was carried at ambient temperature under florescent lighting. All samples were
aseptically prepared in laminar flow hood.
Experimental:
A value of 0.2 ml of tramadol ampouls (50mg/ml) was added to the assigned solution
in a 50 ml piggybag ( normal saline, 5%dextrose, 20% mannitol, ringer, and
compounded sodium lactate) mixed thoroughly and inspected immediately and at 1, 2,
4, 24 hours visually against black and white backgroung for any physical changes(
color, gas production, haze, phase separation, turbidity).A zero time sample of 50
microliter was drawn then at 1, 2, 4, 24 hours and injected directly onto the HPLC
system for tramadol concentration determination.
Adsorption of tramadol to intravenous sets was studied in polyvinyle cellulose (PVC)
tubing. The infusion set was completely filled with preassayed solution of tramadol in
normal saline ( 0.9% NaCl), allowed to stand for six hours at room temperature (
25oc) under florescent lighting. Samples were then drawn and assayed to determine
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the recovered concentration. Adsorption to PVC syringes also was determined by
allowing the tramadol ampoule to stand in the syringes for 24 hours, then sample was
drawn, diluted with normal saline and assayed.
For purposes of this study, admixtures retaining a mean of at least 90% of the original
concentration were defined as stable.
HPLC Assay :
Tramadol concentrations were measured using a specific, accurate and stability
indicating assay.6 The apparatus used from Waters Associates ( Milford,MA,U.S.A )
consist of a model 501 solvent delivery pump, automated gradient controller model
680, tunable detector model 484 at 270 λ, 717 autosampler and 746 data module.
Separation was achieved by using C-18, 5µ Novapak column, the mobile phase
consisted of: 0.01 M phosphate buffer: triethylamin: acetonitrile 83: 1: 17
respectively, adjusted to pH 5.6 with phosphoric acid. Mobile phase was degassed
daily using 0.4 µ membrane filter and isocratically pumped at a flow rate of 1 ml/min
at ambient temperature.The inter- and intra- day studies for tramadol is the same for
two different concentration ( 0.5 and 5.0 mg/ml). The mean relative standard
deviations of the results of within-day precision and accuracy of the drug was less
than 7%.
Results:
No visual or chemical incompatibilities were found when tramadol was mixed with
the above mentioned solutions (table 1).Tramadol- unasyn- normal saline mixtures
stored at room temperature was stable for 24 hours (table 2). When tramadol mixed
with ranitidine in normal saline solution, both were stable for at least 24 hours.
Ondansetron was chemically stable for 24 hours when mixed with tramadol and
stored at 25 oc. Tramadol was also stable when mixed with metronidazole under the
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study condition. Admixtures containing tramadol and acyclovir were incompatible
within the first hour of mixing under the study condition. Adsorption of tramadol to
intravenous sets after 6 hours and to polyvinyle syringes after 24 hours was minimal (
table 3).
Discussion:
Tramadol has been determined to be stable in normal saline, dextrose 5%, mannitol
20%, ringer's solution, and compounded sodium lactate. It is also stable when mixed
with unasyn, ranitidine, metronidazole, and ondansetron. Tramadol adsorption to
intravenous sets and PVC syringes was negligible.
Tramadol has been found to be incompatible with acyclovir and clindamycin when
prepared in normal saline. An immediate precipitate occurred, and tramadol
concentration decreased by more than 60% and 30%, respectively at 24 hours.
Conclusion:
Tramadol injection was compatible with unasyn, ranitidine, and ondansetrone for 24
hours under the study condition. It is stable in intravenous sets and PVC syringes.
Tramadol was incompatible with acyclovir and clindamycin.
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References:
1. Scott LJ & Perry cm. Tramadol: a review of its use in preoperative pain. Drugs
2000; 60(1): 139-176.
2. Preston KL, Jasinski DR & Testa M. Abuse potential and pharmacological
comparison of tramadol and morphin. Drug Alcohol Depend 1991; 27:7-17.
3. Raffa RB, Friderichs E, Reimann W et al. Opioid and nonopioid components
independently contribute to the mechanism of action of tramadol, an "atypical"
opioid analgesic. J Pharmacol Exp Ther 1992;260:275-285.
4. Harati Y, Gooch C, Swenson M et al. Maintenance of the long-term
effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J
Diabetes Complications 2000;14:65-70.
5. Osipova NA, Novikov GA, Beresnev VA et al. Analgesic effect of tramadol in
cancer patients with chronic pain: a comparison with prolonged sction
morphine sulfate. Curr Ther Res 1991;50:812-821.
6. Jianjing L and Yun Y. Patient controlled intravenous analgesia with tramadol
for labor pain relief. Chin Med J 2003;116(11):1752-1755.
7. Zaghloul IY and Radwan MA. High performance liquid chromatographic
determination of tramadol in pharmaceutical dosage forms. J Liq Chrom &
Rel Technol 1997;20(5): 779-787.
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Table 1.
Stability of tramadol in intravenous fluids.
Intravenous fluid
Percentage measured initial concentration remaining at
indicated time ( hours)1
1
2
4
0.9% Sodium chloride
100.5
99.2
100.6
99.6
5% Dextrose
101.3
101.8
101.5
101.9
20% mannitol
99.6
99.6
99.5
100.9
Ringer
99.1
98
99
108
Compounded sodium
101.5
101.4
101.2
101
lactate
1. Mean of two determinations
24
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Table 2.
Stability of tramadol admixtures.
Drug in
Percentage recovered ( hours)1
Concentration
normal saline
1
2
4
24
Unasyn
98.4
93.6
93.5
92.5
Ampicillin
20 mg/ml
Sulbactam
10 mg/ml
Ranitidine
0.5 mg/ml
101
100.2
98.7
99.1
Clindamycin
6 mg/ml
102.5
100
80
65
Ondansetron
16 µg/ml
98.3
96.1
95.1
94.3
Acyclovir
5 mg/ml
80.4
72.7
62.6
34.4
1. Mean of two determinations
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Table 3.
Stability of tramadol in intravenous sets and PVC syringes.
Apparatus
Percentage recovered ( hours)1
6
Accuset
97.8
Venoset
97.3
PVC syringes
1. Mean of two determinations
24
96.3
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Footnotes:
a
Baxter Healthcare Corporation, Deerfield, IL, 60015, lot PS040246, USA.
b
Baxter Healthcare Corporation, lot ZP085563
c
Pharmaceutical Solution Industries, Jeddah, lot NF015AZ, KSA.
d
Pharmaceutical Solution Industries, lot 261214.
e
B. Braun Melsungen AG, D-34209 Melsungen, lot 6233A41A, Germany.
f
Pfizer Ltd, Sandwich, Kent CT13 9NJ, lot 540440, Sandwich 616161, UK.
g
Abbott Hospitals, INC., North Chicago,IL 60064, lot B2436AA, USA.
h
Abbott, lot 16-537DK.
i
Glaxo Laboratories Ltd, Greenford, Middx UB6 OHE, lot B164, UK.
j
Wellcome Medical Division, The Wellcome Foundation Ltd, Crewe Hall,Crewe,
lot B3815A, Cheshire CW1 1UB, UK.
k
Abbott Hospitals, lot 4967
l
I-Med, lot 9200, Country Donegal, Ireland.