Intravenous Lidocaine

Anti-GD2 antibody therapy is a promising experimental treatment that targets gangliosides on disseminated neuroblastoma cells as well as normal nervous tissue [1-4]. The infusion of the antibody is associated with pain in the abdomen, back, and extremities, which appears within 20 minutes after the initiation of the antibody infusion and ceases shortly after ending the infusion. Pain is conventionally controlled with moderate to large doses of morphine. Because of the nature of the pain syndrome resulting from anti-GD2 therapy, we had reason to believe that small-dose intravenous (IV) lidocaine might be an effective analgesic and, consequently, may reduce opioid requirements. Case Reports All work described herein was approved by our institutional review board. Five children (three female and two male) with neuroblastoma undergoing immunotherapy with anti-GD2 antibody (ch14.18) were recruited for the study. The average subject's age (+/- SD) was 4.9 +/- 1.34 yr (range 4-7 yr). This was an open-label study. The neuroblastoma therapy consisted of four daily infusions of ch14.18 at 50 mg [center dot] m-2 [center dot] d-1 over 5 h in combination with 14 daily subcutaneous injections of granulocyte macrophage colony-stimulating factor at 10 micro g [center dot] kg-1 [center dot] d-1. Because the patients received multiple courses of therapy (nine in one patient), it was possible to compare the results of therapy in the same patient. Each course of therapy was separated by at least 1 mo. All patients in this study had received prior immunotherapy with an IV morphine infusion and prn morphine boluses for pain control. Records were reviewed to determine the amount of morphine that they had received. For subsequent anti-GD2 treatments, all patients received at least one IV lidocaine infusion for pain control. Heart rate, blood pressure, respiratory rate, and oxygen saturation were recorded every hour during the morphine and lidocaine infusions. Subjects received either lidocaine (2 mg/kg) or morphine (0.1 mg/kg) infused over 30 min before antibody therapy, followed by a continuous infusion of lidocaine (1 mg [center dot] kg-1 [center dot] h-1) or morphine (0.05-0.1 mg [center dot] kg-1 [center dot] h-1), respectively. The infusion was maintained for the duration of the antibody infusion and discontinued 2 h after its completion (7 h). Pain scores were rated on a scale of 1-7 (faces scale) [5] every 2 h and at the conclusion of the 7 h. Breakthrough pain (pain score >2) was managed with IV morphine (0.05 mg/kg) every 2 h or as needed. If the score was >2, the infusion was continued until the pain score had decreased to 2 or less. In subjects who received lidocaine, blood samples were drawn for plasma lidocaine measurement on completion of the antibody therapy. Total morphine requirement was measured over the course of therapy. The level of consciousness and the mobility level were measured at the end of the antibody infusion on a scale of 0-3. Nausea and emesis episodes were measured over a 24-h period. Average daily lidocaine doses were 170 +/- 40 mg (8.9 +/- 1.1 mg/kg). Average daily lidocaine plasma levels ranged from 0.55 +/- 0.17 to 2.3 +/- 2.05 micro g/mL. There were no significant differences in the pain scores between the two groups. No patient required continuation of the lidocaine after the 7.5 h, as delineated by the protocol (pain scores remained <or=to2); however, three patients (one course per patient) required continuation of the morphine infusion for the entire 4 days of therapy. Although there was no significant difference in morphine requirements for breakthrough pain between the groups, there was much greater total morphine consumption in the morphine group (Figure 1). In addition, in the lidocaine group, there was a significant reduction in morphine requirements on Days 2-4 compared with Day 1 (Figure 1).Figure 1: Comparison of daily morphine requirements for pain control in patients receiving an intravenous morphine versus intravenous lidocaine infusion for pain control during anti-GD2 infusion. **P < 0.01 between groups. #P < 0.05 in lidocaine group on Days 2-4 compared with Day 1.Ch14.18 therapy resulted in a significant increase in baseline heart rate over the 4-day period, with the increase being greater for the morphine group. There was no significant change in blood pressure at any time. IV lidocaine resulted in a significant improvement in mobility on Day 4 only (Figure 2). Lidocaine was associated with less nausea on Days 1 and 2; however, the lidocaine-treated patients also exhibited increased emesis on Day 4.Figure 2: Comparison of daily mobility scores in patients receiving an intravenous morphine versus intravenous lidocaine infusion for pain control during anti-GD2 infusion. Mobility was scored as follows: ambulating = 0, walking with help = 1, confined to a chair = 2, confined to bed = 3. *P < 0.05 between groups.Discussion Overall, the patients receiving lidocaine did better than those receiving morphine alone. The morphine consumption and mobility changes corresponded well with the plasma lidocaine levels. When the lidocaine level increased (Days 2 and 4), the morphine consumption decreased and the mobility improved. When the plasma levels decreased (Day 3), the morphine consumption slightly increased and the mobility slightly worsened. In addition to the characteristics described in the introduction, this pain syndrome is also associated with hypertension and increased heart rate, most likely secondary to the pain that the patients experience [1,6,7]. The heart rate did not return to baseline until two days after completion of the four-day course of therapy. Whether the increase in heart rate represents a stress or pain response was not obvious in this study group (pain can be difficult to measure in the pediatric population). The observation that the lidocaine treatment blunted the increase of heart rate suggests that at least a component of it was related to pain; however, lidocaine can also modify heart rate responses by its effects on vascular tone and baroreceptor functioning, independent of its antinociceptive effects. The mechanism of anti-GD2 antibody-induced pain is unclear. Of note is that anti-GD2-induced pain is more severe and lasts longer in adults than in children. This is interesting because the relative amounts of gangliosides (including GD2) synthesized in the b-ganglio pathway increases during maturation relative to those made in the A-synthesis pathway [8]. Interference with, or binding to, GD2 ganglioside seems to play an important role in the development of the pain syndrome of this immunotherapy. Activation of the complement cascade could result from anti-GD2 antibody binding to its epitope on the nerve in the same way that it is thought to follow binding to the neuroblastoma cells. This pain syndrome is similar to other neuropathic pain syndromes, which are relatively resistant to opioids. Recent studies have shown systemic lidocaine to be effective in the treatment of several neuropathic pain disorders at doses that do not produce complete anesthesia [9-14] and at plasma concentrations below those required to block of axonal conduction [15,16]. A negative impact that we observed with systemic lidocaine compared with morphine alone was a significant increase in emesis on Day 4 only. This corresponded with the peak daily plasma lidocaine level, which may have been a contributing factor. In summary, the use of IV lidocaine for treating pain secondary to anti-GD (2) antibody therapy may be a useful alternative to large-dose morphine. Although systemic lidocaine is useful in these patients, it does not completely negate the use of opioids. Rather, it decreases the amount of opioid required and thus decreases the side effects associated with morphine. Further investigation is required to determine the exact nature of this pain syndrome and its treatment. The authors thank Steve Laitin, MD, for his assistance in this project and Linda Sutherland for her assistance in the preparation of the manuscript.