Abstract
Objectives
To determine if the intravenous co-administration of equal volumes of lidocaine and nalbuphine, with undiluted normal saline, prevents injection pain caused by nalbuphine.
Methods
Eighty adult patients who were scheduled for minor surgeries under general anesthesia delivered via a laryngeal mask airway (LMA) were enrolled in this prospective, randomized, single-blind clinical trial. In the saline group (control) (n = 40), 1 mL (10 mg) nalbuphine was diluted with 9 mL normal saline. In the lidocaine group (experimental) (n = 40), 1 mL (10 mg) nalbuphine was diluted with 1 mL lidocaine (20 mg). The two respective nalbuphine solutions were injected into the cephalic vein at a rate of 20 mL/minute (0.33 mL/second). Pain scores were categorized into five grades. Pain responses upon intravenous injection of nalbuphine, site of cannulation, size of the catheter, and hemodynamic responses to nalbuphine were also recorded.
Results
Overall, the median pain score of patients in the lidocaine group was lower than that of the saline group (p < 0.001). In addition, the incidence of injection pain was lower in the lidocaine group than the saline group (2.5% vs. 30%, p = 0.001).
Conclusion
A solution of equal volumes of lidocaine and nalbuphine can decrease intravenous nalbuphine-induced injection pain.
Keywords
injections; intravenous; pain; lidocaine; nalbuphine;
1. Introduction
Nalbuphine—an opioid, kappa receptor agonist and mu receptor antagonist—is structurally similar to oxymorphone and naloxone and has been shown to be a useful analgesic agent in various clinical settings, including prehospitalization care for the treatment of trauma-induced acute pain,1, 2, 3 peri-operative care for the attenuation of postoperative pain,4, 5, 6, 7 and as effective adjuvant for anesthetic-induction agents.8, 9, 10 In addition, it can be used to prevent adverse narcotic-induced effects.11, 12
However, when nalbuphine is administered intravenously, it causes severe pain at the injection site.13 This injection pain may cause distress in patients and be problematic for care providers in operating rooms. In order to avoid injection pain, it is common practice to dilute nalbuphine with normal saline (NS) before use. The incidence of injection pain following the injection of pure nalbuphine is as high as 61%.13 Although it has been shown that saline-diluted nalbuphine containing lidocaine could, to some extent, reduce the severity of injection pain, intravenous injection of NS alone induces pain in 15% of patients.13 We hypothesized that the co-administration of straight nalbuphine and lidocaine could prevent or reduce nalbuphine-induced injection pain. This combination can also be easily prepared. Thus, the aim of this study was to determine if the co-administration of pure, intravenous nalbuphine and lidocaine (without NS) could attenuate the severity or reduce intravenous nalbuphine-induced injection pain during the induction of general anesthesia.
2. Materials and methods
The study was approved by the institutional review board of Kaohsiung Municipal Hsiao-Kang Hospital (KMHK-IRB-96012). Eighty adult patients (age range: 20–60 years) classified as ASA physical status I or II and were scheduled for minor surgeries under general anesthesia delivered via a laryngeal mask airway (LMA) were enrolled in this prospective, randomized, single-blind trial. Informed consent was obtained from all patients. Patients with a history of vasculitis, cephalic vein thrombophlebitis, peripheral vascular diseases, diabetes, and hypertension were excluded from this study.
A venous cannula was inserted into the cephalic vein through either the back of the hand or the forearm for 2 hours before the patient was sent to the operating room. To determine that NS pain is not concurrently responsible for injection pain, 5 mL NS (1 mL/sec) was administered to patients before induction to see whether NS would also result in pain. Those who complained of a painful sensation were excluded from this study. After arriving at the operation room, the patients were premedicated with intravenous midazolam (0.03 mg/kg). Standard intraoperative physiological surveillance, including noninvasive arterial blood pressure measurement, electrocardiogram, peripheral arterial oxygen saturation, and end-tidal carbon dioxide monitoring were applied. The dosage of nalbuphine was set at 0.1 mg/kg. The protocol of this study is shown as Fig. 1. In brief, patients were randomly assigned to two groups: the saline group (n = 40) or the lidocaine group (n = 40), according to a dictate that was sealed in an envelope. In the saline group, 1 mL (10 mg) nalbuphine (osmolarity: 345 mOsm/L; pH: 3.5–3.7) was diluted with 9 mL NS (osmolarity: 309 mOsm/L; pH: 5.5–7.0) in order to make a concentration of 1 mg/mL in a 10-mL syringe. In the lidocaine group, 1 mL (10 mg) nalbuphine was mixed with an equal volume of 2% lidocaine (20 mg; osmolarity: 150 mOsm/L; pH: 6.5–7.0) in order to make a concentration of 5 mg/mL nalbuphine in a 10-mL syringe. The injection rate was 20 mL/min (Orchestra Base Primea, Fresenius Kabi, Germany) for both groups, such that nalbuphine was administered at a rate of 0.33 mg/second to the saline group and 1.67 mg/second to the lidocaine group. Following the intravenous administration of nalbuphine, the reported injection pain score was categorized into five grades (Table 1), as modified from Cheong et al.14 An experienced anesthesiologist, who was blinded to the nature of the solution, administered the solution and assessed the pain score. If the patient complained of moderate or severe injection pain, 5 mg/kg thiamylal and 8% sevoflurane in oxygen were administered simultaneously in order to relieve discomfort. In our study, painless injection was scored as grade 1 or 2, while painful injection was scored as grade 3–5. Hemodynamic parameters, including mean arterial blood pressure and heart rate, were measured and recorded 3 minutes before and 1 minute after the administration of nalbuphine. For those who did not show moderate or severe injection pain, 5 mg/kg thiamylal was administered 1–2 minutes after the intravenous administration of nalbuphine in order to initiate induction. All patients were then subjected to LMA insertion after inhaling 4–8% sevoflurane in oxygen for 2 minutes. To assess the development of thrombophlebitis in the cephalic vein at the site of cannulation, a modified scale based on the severity of symptoms and signs in the recovery room was used15: i.e., grade 0 (no symptoms), grade 1 (pain or erythema at the intravenous injection site), grade 2 (pain at the intravenous injection site with erythema or swelling), grade 3 (pain at the intravenous injection site with erythema, swelling, or a palpable venous cord), and grade 4 (pain at the intravenous injection site with erythema, swelling, and a palpable venous cord). The assessment of thrombophlebitis was carried out at two time points: immediately after the patient was transferred to the recovery room following the operation and the next morning. Assessment was conducted by a nurse who was blinded to this study.
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Power analysis was performed to determine the size of each group. By referencing the report by van den Berg et al13 and defining a type I error (α) as 0.05 and the power as 0.9, the sample size was determined with a difference in the pain responses of at least 50% between groups and the percentage of painful injection responses in the lidocaine group within 25%. The results yielded 38 patients in each group. Differences in the continuous variables between groups were evaluated using the Student t test or Mann-Whitney U test. Differences in the categorical variables between groups were tested with the Chi-square or Fisher’s exact test. Results were considered statistically significant if p < 0.05.
3. Results
Demographic data of the two groups were similar, as shown in Table 2. The hemodynamic responses associated with the intravenous administration of nalbuphine were also comparable between the two groups (Table 3). No patient in this study sustained significant thrombophlebitis (grade 2–4), when assessed at the two postoperative time points.
As shown in Table 3, the median pain score of the lidocaine group was lower than that of the saline group (p < 0.001). In addition, patients in the lidocaine group had a far lower incidence of injection pain in comparison with the patients in the saline group (2.5% vs. 30%, p = 0.001). When evaluating the association between the cannulation site and injection pain between the two groups, the incidence of injection pain was found to be significantly lower in the lidocaine group compared with the saline group; nalbuphine was administered into the cephalic vein of the dorsal hand (p = 0.01) or the forearm (p = 0.032), respectively. However, the administration of nalbuphine at different cannulation sites showed similar incidences of injection pain across group comparisons (saline group, p = 0.285; lidocaine group, p = 1.0).
4. Discussion
Because nalbuphine is an injectable agent, it is not surprising that it may induce injection pain during intravenous administration. In order to minimize potential injection pain, diluting nalbuphine with saline before use is a common practice. However, as shown in this study, even when this method is used, the incidence of nalbuphine-induced injection pain is still around 30%. Our study shows that pure nalbuphine, when mixed with an equal volume of pure lidocaine, could dramatically reduce the incidence of pain to 2.5%. In addition, the preparation of such a mixture is easy and can be quickly performed. Therefore, our study demonstrates that the co-administration of pure nalbuphine and lidocaine can be used to alleviate intravenous nalbuphine-induced pain in anesthetic practice.
Van den Berg et al13 reported that the addition of lidocaine (2 mg/mL) to nalbuphine-diluted saline (2 mg/mL) could also reduce nalbuphine-induced injection pain. Their study, however, differs from ours. First, in our present study, pure lidocaine (10 mg/mL) and nalbuphine (5 mg/mL) were used in equal volumes, so saline dilution was not required. Second, potential irritation by saline was avoided.13 Third, the use of pure lidocaine and nalbuphine with undiluted saline is much simpler and saved time. Fourth, it is easy to maintain a stable injection flow rate when a standardized solution is administration to each patient. Fifth, only one of 40 patients in our lidocaine group reported injection pain and none showed painful withdrawal behaviors. However, in the study by Van den Berg et al, 12 out of 33 patients reported injection pain and two showed withdrawal behaviors. The excellent results in our patients could be attributed to the higher concentration of lidocaine (10 mg/mL) that was used in our study.
The results of this study are somewhat in accordance with previous studies that demonstrated that lidocaine, when co-administered with propofol16, 17, 18, 19 or rocuronium,20, 21 is able to reduce injection pain. Lidocaine reduces the nalbuphine-induced pain by blocking nociceptive receptors,22 stabilizing the kinin cascade, and inhibiting the activation of the plasma kallikrein-kinin system during injection.23 However, lidocaine should be premixed with the injection solution before intravenous administration in order to ensure maximum patient comfort.24
The acidity of the solution is also a factor that induces injection pain. The pH of nalbuphine hydrochloride (10 mg/mL) is around 3.5, which, if not diluted, can cause painful venous irritation. According to the study by Klement and Arndt,25 nalbuphine causes pain when the pH of the injection solution is below 4 or above 11, and the pain reaches its maximum level (a score of 100 on the visual analogue scale) when the pH of the solution is 2 or 13. Solutions outside of physiological pH evoke pain due to the physiochemical properties of their solvents, rather than the algogenesis of the drugs.25 The pH of the saline used to dilute nalbuphine in our saline group was determined to be near 4.5, which might induce pain or unpleasant side effects during injection. The pH of the mixture of pure nalbuphine and lidocaine in the lidocaine group of our study was determined to be 3.8–4.0, which accounts for the fact that there was still one patient in this group who reported injection pain, in spite of the analgesic effect of lidocaine. Accordingly, to further decrease the incidence of injection pain induced by bolus nalbuphine, we suggest that a multiformat strategy be applied in order to enhance the analgesic effects of lidocaine, such as pretreatment with lidocaine before nalbuphine injection or the use of Bier’s blocking technique with a rubber tourniquet.26, 27 However, further investigations are required to compare these methods.
There are some other factors associated with injection pain, such as the osmolarity and ingredients of the injected solution. The osmolarities of the solutions in our study were 247.5 mOsm/L for the lidocaine-nalbuphine mixture and 312.6 mOsm/L for saline-diluted nalbuphine, both of which are far below the threshold of 2000 mOsm/L that could induce injection pain.25 Accordingly, we believe that osmolarity was not a confounding factor in our study. Even though each vial of nalbuphine contains methylparaben and propylparaben as preservatives, neither of these has ever been reported to cause injection pain.
The primary limitation of this study is that we only measured immediate pain upon injection and neglected to measure any pain that presented after the injection, which sometimes occurs.28 Second, our study was designed to eliminate the confounding effects of painful sensation; thus, we excluded patients with peripheral vascular diseases. Consequently, the conclusion of the study cannot be extrapolated to all patients who might receive nalbuphine.
In conclusion, we found that the co-administration of pure nalbuphine and lidocaine can lower the incidence of injection pain that results from nalbuphine alone, as compared with saline-diluted nalbuphine. Therefore, this novel method of mixing equal volumes of pure lidocaine and nalbuphine (without saline dilution) could effectively reduce the incidence of nalbuphine-induced injection pain. This simple method is a practical way to minimize nalbuphine-induced injection pain.
Acknowledgments
The authors would like to thank Richard H. Davis for his assistance with editing this manuscript.