Compatibility of tramadol injection with selected drugs and solutions
Tramadol hydrochloride is a centrally acting
synthetic analgesic with a dual mechanism of action. Tramadol and its Odesmethyl metabolite (M1)
bind to opioid receptors, with M1 having a 200-fold higher affinity for binding
to these receptors. Tramadol has also been shown to inhibit the uptake of norepinephrine
and serotonin, suggesting that its antinociceptive activity is mediated by both
opioid and nonopioid mechanisms. In patients with diabetic neuropathy, therapy
with oral tramadol resulted in low pain scores and high painrelief scores. Tramadol
produced effective analgesia with minimal adverse effects in cancer patients
with chronic pain.
Tramadol is also a useful alternative in patient-controlled epidural
analgesia when patients cannot receive combined spinal? epidural analgesia for
labor pains. There are some clinical situations in which tramadol must be
combined with other drugs, such as for patients with postoperative pain who
require both a painkiller and an antibiotic or when tramadol is used as an
adjunct to analgesic-supplemented anesthesia for certain surgical procedures.
In addition, patients receiving tramadol are likely to receive other i.v.
medications concurrently. There may be a need for tramadol and other agents to
be administered through the same intravenous line.
Tramadol can be administered
by i.v. bolus injection and by i.v. infusion. The objective of this study was
to investigate the compatibility of tramadol injection with different infusion solutions
and in admixtures with five commonly used injectable medications:
(1)
ampicillin?sulbactam,
(2) ranitidine,
(3) clindamycin,
(4) ondansetron,
(5)acyclovir.
In addition, the adsorption of tramadol to i.v. infusion sets and syringes were investigated at room temperature and under fluorescent lighting.
Methods.
Preparation of stock solutions.
Tramadol hydrochloride 1-mg/mL stock solutiona and metoclopramide 1-mg/mL solutionb as the internal standard (IS) were prepared in deionized water (high-performance liquid chromatography [HPLC] grade) and frozen at ?20 ?C. Weekly dilutions were made using deionized water to produce tramadol solutions with concentrations of 0.1?10 μg/mL and maintain a constant concentration of 0.5 μg/mL of the IS. Samples of each standard were injected into the HPLC system and assayed in triplicate to generate the standard curve.
All standard samples and solutions were filtered using a 0.45-μm membrane filter.
Admixture preparation and analysis.
A 0.4-mL portion of tramadol hydrochloride i.v. injection 50 mg/mL was added to 50-mL polyvinyl chloride (PVC) infusion bags containing 0.9% sodium chloride (NS), 5% dextrose, 20% mannitol, lactated Ringer?s solution, or compounded sodium lactate injectionsi (n = 4). The nominal concentration of tramadol was 0.4 mg/mL in all prepared solutions. Two of each mixed solution were stored at either 4 ?C or room temperature under normal fluorescent light. The stability of tramadol in NS was studied in the presence of secondary medications such as ampicillin?sulbactam, ranitidine hydrochloride, clindamycin phosphate, ondansetron hydrochloride,and acyclovir sodium. Drugs supplied in lyophilized form were reconstituted with sterile water for injection according to the manufacturer?s recommendations, while drugs in solution form were added directly to the 50-mL infusion bag.
The nominal concentration of tramadol was kept at 0.4 mg/mL in NS throughout the study. The concentrations of the drug tested with tramadol were prepared according to the concentrations used in the clinical setting.
The physical and chemical stability of tramadol in the secondary drug admixtures were studied for 24 hours. Mixtures were visually inspected immediately after preparation (0 hour) and at 1, 2, 4, and 24 hours against a black-and-white background for any physical changes, including color, gas production, haze, phase separation, and turbidity. A 1-mL sample was drawn from each bag at 0, 1, 2, 4, and 24 hours and diluted to 100 mL with deionized water containing 0.5 μg/mL of IS. Solutions were filtered through a 0.45-μm membrane filter. Next, 50-μL samples (n = 3) were injected into the HPLC system to determine the tramadol concentration of each mixture. Concentrations of the secondary drugs were not measured.
Adsorption of tramadol to i.v. sets was studied using two brands of PVC tubing (n = 2).o,p The infusion sets were completely filled with preassayed solution of tramadol 0.4 mg/ mL in NS and allowed to stand for 6 hours at room temperature under fluorescent lighting. Samples were then drawn and assayed to determine the remaining tramadol concentration.
Adsorption to PVC syringes also was determined in duplicate by allowing the tramadol solution 50 mg/mL to stand in the syringes for 24 hours and then diluting 100-μL samples to 100 mL with deionized water, yielding a theoretical final concentration of 50 μg/mL. A 1-mL sample of the solution was mixed with 2.5 mL (5 μg/mL) of the IS and brought to 10 mL with deionized water in a volumetric flask. Samples of 50 μL of the above solution were injected in triplicate into the HPLC system. For purposes of this study, admixtures retaining a mean of at least 90% of the original actual concentration were defined as stable.
HPLC assay. Tramadol concentrations were measured using a specific, accurate, and stability-indicating assay. ?The instrumentation included a solvent-delivery pump,q an automated gradient controller, a tunable absorbance ultraviolet-light detectors set at 270 nm, an autosampler, and a recording integrator. Separation was achieved by using a C18, 5-μm column equipped with a 5-μm guard column. The mobile phase consisted of 0.01 M phosphate buffer, triethylamine, and acetonitrile in a 82:1:17 ratio, respectively, adjusted to pH 5.6 with phosphoric acid immediately before the addition of acetonitrile. Mobile phase was degassed daily using a 0.22-μm membrane filter and isocratically pumped at a flow rate of 1 mL/min at ambient temperature. The run time was 18 minutes. The interday and intraday studies for tramadol were the same for each concentration (0.5 and 5.0 mg/mL).
The relative standard deviations of the results of within-day precision and accuracy of the drug at nominal concentrations of 5 μg/mL were 6.4% and 6.9%, respectively. The approximate retention times for tramadol and metoclopramide were 6.7 and 4.6 minutes, respectively.
The HPLC method was validated as stability indicating by accelerated decomposition of tramadol.7 Tramadol 5 μg/mL was stable for at least four weeks when stored at 4, 25, and 50 ?C. In addition, tramadol was stable at extreme pH conditions. No tramadol decomposition products were observed in any chromatogram during the validation.
Data analysis. The quantitation of the drug was performed on the basis of peak area ratios in the chromatogram. The calibration curve of tramadol was linear over the concentration range of 0.1?10 μg/mL. The t test was used to examine the concentration difference at each day, and one-way analysis of variance was employed to evaluate the reproducibility of the assay. The significance level of α error was less than 0.05.
Stability was defined as retention of ≥90% of the initial tramadol concentration. For the incompatibility study, duplicate determinations were made from a single sample that was withdrawn from two independently prepared admixtures and solutions stored in infusion sets and syringes at each time interval.
Table 1.
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Results. No visual incompatibilities were found when tramadol was mixed with the i.v. injection solutions at room temperature and 4 ?C. More than 99% of the initial concentration was detected 24 hours after mixing with all studied solutions at both temperatures. Table 1 displays the data obtained at room temperature.
The results of the stability testing at 4 ?C were not reported because no changes were detected at this temperature.
The percentage of recovered tramadol was considerably higher when mixed with lactated Ringer?s solution than with other solutions; however, this finding could not be explained, since samples of Ringer?s solution alone showed no peaks under the tested conditions.
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Figure 1.
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Figure 1 represents a typical chromatogram of tramadol stored in NS for 24 hours at room temperature, where the retention times of tramadol and the IS were 4.6 and 6.7 minutes, respectively. HPLC analysis demonstrated no evidence of tramadol degradation products in any sample analyzed.
The compatibility of tramadol when mixed with different drugs in NS is shown in Table 2.
Table2
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The decrease in tramadol concentrations in the admixture with ampicillin? sulbactam was not accompanied by the appearance of any degradation peaks. When mixed with clindamycin, tramadol was stable for only 2 hours and then degraded to 65% of the initial concentration by 24 hours, and a precipitate appeared. Interestingly, no decomposition peaks were detected on the chromatogram in this admixture despite the great loss of tramadol concentration. Thus, the decomposition peaks could have eluted earlier with the solvent front.
Figure 2
Tramadol was chemically stable for 24 hours when mixed with ondansetron and stored at room temperature. An ondansetron peak was eluted in the HPLC chromatogram after 14.5 minutes and did not interfere with the tramadol peak (Figure 2). Admixtures containing tramadol and acyclovir were incompatible within the first hour of mixing under the study conditions and were accompanied by precipitation.
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Adsorption of tramadol to intravenous sets was minimal after six hours, the length of time an i.v. tubing set is used at our institution (Table 3). More than 95% of the original solution was measured at the end of the study in both infusion sets. There was no evidence of precipitation on visual inspection of tubing sets. Drug adsorption to PVC syringes after 24 hours was minimal, with 96.3% of the initial tramadol concentration recovered.
Table 3
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Discussion. Tramadol is available in more than 70 countries, including the United States. It is a centrally acting, synthetic analgesic. It has weak opioid agonist properties and also has effects on neurotransmitter reuptake.8 Tramadol demonstrated its effectiveness in both acute and chronic pain ?states. Aside from its proven clinical efficacy, tramadol is a safe drug, as respiratory depression, adverse cardiovascular effects, and its potential for drug abuse and dependence are of minor clinical relevance.9
Conclusion. Tramadol injection was stable when mixed with NS, 5% dextrose injection, mannitol 20%, lactated Ringer?s solution, compounded sodium lactate, ampicillin?sulbactam, ranitidine, and ondansetron for at least 24 hours at 4 ?C and at room temperature. Tramadol showed little absorption to intravenous sets and PVC syringes. However, tramadol was incompatible with acyclovir and clindamycin, and their mixing should be avoided.
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