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CLINICAL STUDIES |
From the Departments of Clinical Immunology & Analgesia, Clinical Pharmacology, and Biostatistics, Merck Research Laboratories, Rahway, New Jersey, and Clinical Drug Metabolism, West Point, Pennsylvania.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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2 third molars, were randomized (2:2:1:1) to lidocaine (4 mg/kg; maximal dose 300 mg), oxycodone/acetaminophen (10/650 mg), placebo, and active placebo (diphenhydramine, 50 mg). Lidocaine provided a modest degree of pain relief. Predefined endpoints of total pain relief and sum of pain intensity at 2, 4, and 6 hours showed numerically, not statistically significantly, greater pain relief versus placebo. A significantly greater effect over placebo was observed in peak effect and at shorter time points (30 minutes and 1 hour), consistent with the pharmacokinetic profile (plasma concentration of 
2 µg/mL). Oxycodone/acetaminophen provided significantly greater analgesia versus placebo, validating study conduct, and significantly greater pain relief was observed versus lidocaine, which is consistent with a smaller portion of dental extraction pain being of neuropathic origin.
Key Words: Neuropathic pain • dental impaction pain • lidocaine • pain model
The use of the dental impaction model in assessing drugs with potential efficacy in the treatment of neuropathic pain would have many advantages. For example, (1) the subjects studied are young and healthy adults, (2) the pain is consistent in nature with low variability between subjects, and (3) the magnitude of the pain is high, with both onset and duration of pain being reproducible in most subjects (ie, subjects generally request analgesics within 2 to 3 hours after surgery, and the principal need for analgesic treatment is over the first 24 to 48 hours).
This pilot study was designed to assess the analgesic effect of intravenous lidocaine, a nonspecific Na-channel blocker, on pain following the removal of impacted third molars. Lidocaine, when given intravenously, has demonstrated efficacy in the treatment of postoperative pain1,3 and in various types of neuropathic pain (eg, thalamic pain, trigeminal, postamputation pain).4-8 Lidocaine is known to cause noticeable side effects; therefore, to ensure blinding, an active placebo group (diphenhydramine, ie, an agent without analgesic properties and with side effects similar to that of lidocaine) was included in addition to a standard placebo group.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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5 to 7 days after treatment visit). This single-center study was conducted at the Dental Center, PPD Development (Austin, Tex). Protocol and consent form were approved by the central institutional review board, Research Consultants' Review Committee (Austin, Tex). All subjects gave written informed consent before any procedures were performed.
Study Population
Eligible subjects were healthy men and women, 18 to 45 years of age, who had 2 or more third molars to be removed, of which at least 1 was either partially or completely embedded in mandibular bone. The degree of impaction for each tooth that was to be removed was evaluated using an Impaction Score; each tooth was rated from 1 to 4 using the following criteria: (1) erupted in tissue; (2) broken, soft tissue; (3) partial boney impaction; and (4) full boney impaction. Subjects with abnormal findings at the physical examination, abnormal laboratory safety tests, and an abnormal electrocardiogram (ECG; resting heart rate of 
45 bpm, PR interval of 200 msec, or a QRS duration of 115 msec) at prestudy or before dosing were excluded. Women of childbearing potential with a positive pregnancy test at the prestudy visit or the day of surgery (dosing) were also excluded. All women agreed to either remain abstinent or use appropriate contraception starting at the screening visit and through 7 days postdose. Subjects who required treatment for any chronic condition were excluded, whereas subjects who used analgesics (eg, aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs], opioids) sporadically were permitted to participate. If used, the analgesic must have been stopped within 6 to 72 hours before the surgery, depending on the half-life of the drug. Lidocaine with epinephrine was the local anesthetic used in this study; all subjects also received nitrous oxide. The subjects remained in the clinic for at least 6 hours postdose; they were required to have normal ECG and vital signs (blood pressure, heart rate, and respiratory rate) before they were discharged from the clinic.
Study Medication, Rescue Medication, Randomization, and Blinding
Subjects who developed moderate or severe pain within 5 hours of surgery received, in a blinded fashion, intravenous lidocaine, oxycodone/acetaminophen, active placebo (intravenous diphenhydramine and placebo tablets), or placebo (saline and placebo tablets) according to a computer-generated allocation schedule in a ratio of 2:2:1:1. All subjects were administered 2 tablets (taken with water) and an intravenous (IV) bolus (over 2 minutes) followed by a continuous infusion (over 60 minutes). The lidocaine dosing regimen was selected based on the maximal approved dose (300 mg) and pharmacokinetic modeling using a 2-compartment model9: a bolus of 1.25 mg/kg lidocaine was estimated to result in peak plasma concentrations of 2 to 3 µg/mL, and a continuous lidocaine infusion of 2.75 mg/kg following the IV bolus is expected to maintain the plasma lidocaine concentrations above 1.2 µg/mL for 2 hours (Figure 1a). The lidocaine group also received grossly matching placebo tablets. The oxycodone/acetaminophen group received 2 tablets of oxycodone/acetaminophen (10/650 mg), a bolus, and continuous infusion of saline. The placebo group received grossly matching placebo tablets, as well as a bolus and continuous infusion of saline. The active placebo group received grossly matching placebo tablets and a bolus of 10 mg diphenhydramine followed by a continuous infusion of 40 mg diphenhydramine. The intravenous study drugs were administered using a Baxter AS 50 pump. Subjects were monitored for ECG changes via 5-lead telemetry starting 30 minutes before dosing and through 6 hours postdose. A physician was present throughout the administration of study drug. To ensure that blinding was maintained, study medication was administered by a staff member, who was not involved in the study conduct.
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Rescue medication (acetaminophen/hydrocodone 500/5 mg) was available should the subjects not obtain pain relief from the study drug; however, the subjects were encouraged to refrain from using rescue medication, if possible, until after 90 minutes postdose, to allow the study medication to manifest its effect.
Lidocaine Plasma Concentration
Blood samples, for the determination of lidocaine plasma levels, were collected from all subjects before dosing, 10 minutes after start of the intravenous infusion, at the completion of the infusion (approximately 60 minutes postdose), and approximately 120 minutes postdose. The plasma samples were frozen and shipped to a central laboratory for determination of lidocaine levels. Only plasma samples from the subjects who received lidocaine were assayed.
Plasma samples collected following each lidocaine dose were assayed for lidocaine concentrations (PPD Development Middleton, Wis) and analyzed. Analysis was accomplished using high-performance liquid chromatography (HPLC) with ultraviolet absorbance detection. The HPLC lidocaine assay used prilocaine as the internal standard, and the ultraviolet absorbance wavelength used was 210 nm. The sample preparation for liquid chromatography involved extraction into hexane, drying under vacuum, and reconstitution with mobile phase. The calibration curve ranged from 2 to 500 ng/mL. Precision and accuracy were determined by replicate (n = 3) analysis of quality control samples at 3 concentrations spanning the calibration range. Interassay accuracy (expressed as percent difference of the mean value for each quality control from the theoretical concentration) ranged from 1% to 33%. Interassay precision (expressed as percent coefficient of variation) was < 20%.
Diary Card
Subjects rated the pain intensity (none, slight, moderate, or severe) and the pain relief they experienced (none, a little, some, a lot, and complete) at 12 prespecified time points (5, 10, 20, 30, 45, 60, and 90 minutes and 2, 3, 4, 5, and 6 hours after completion of the bolus injection) and recorded the scores on a diary card. At 2, 4, and 6 hours postdose, they also rated the study medication using a scale of poor, fair, good, very good, or excellent. The subjects also recorded when they took rescue medication.
Efficacy Endpoints
Pain relief and pain intensity scores, respectively, were used to calculate the overall analgesic effect: the weighted total of pain relief scores over the first 2, 4, and 6 hours (TOPAR2, TOPAR4, and TOPAR6) and the weighted sum of pain intensity difference scores over the first 2, 4, and 6 hours (SPID2, SPID4, and SPID6). TOPAR2 was the primary endpoint, selected based on the estimated half-life for intravenous lidocaine. In addition, TOPAR4 and TOPAR6 were evaluated because the recommended dosing intervals for oxycodone/acetaminophen are 4 and 6 hours. Global evaluation at 2, 4, and 6 hours also estimated the overall pain relief over the respective time periods. Other endpoints assessed the peak analgesic effect: the maximum pain relief and maximum pain intensity difference (PID) during the 6 hours post-dose using a 0 to 4 scale and –1 to 3 scale, respectively. The duration of the analgesic effect (median time to the first dose of rescue medication) and the percentage of subjects requesting rescue medication were also determined.
Tolerability Assessment
On the day of dosing, the tolerability of the study drugs was assessed by ECG (5-lead telometry), which was started 30 minutes before the start of infusion and for the next 6 hours. In addition, heart rate and blood pressure were measured hourly after infusion. Adverse experiences were reported spontaneously, which the investigator determined in a blinded fashion whether it could have been caused by the study drug.
Statistical Analyses
The efficacy analysis was a modified intention-to-treat analysis and included all randomized subjects who had a baseline pain intensity score and reported at least 1 postdose pain and/or pain relief assessment. All randomized subjects were included in the tolerability evaluation. TOPAR2, TOPAR4, and TOPAR6 were analyzed by using a parametric analysis of variance (ANOVA) model. The ANOVA model, Cox proportional hazards regression model, or logistic regression model was used in the analyses of the other endpoints, as appropriate. In each model, treatment was included as a factor. Post hoc analyses were performed to allow additional assessment of the treatment effect at earlier time points using similar approaches.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Lidocaine Versus Placebo
The concentration versus time curve of the lidocaine plasma concentration for subjects who received intravenous lidocaine is shown in Figure 1b. The predose lidocaine plasma concentration was slightly elevated (0.8 µg/mL), which was not unexpected because all subjects received lidocaine as the local anesthetic for the dental surgery. The observed maximal lidocaine concentration (2.3 µg/mL; Figure 1b) was similar to the projected maximal concentration of 2.5 µg/mL (Figure 1a).
Intravenous lidocaine provided numerically but not statistically greater pain relief compared with the 2 placebo groups, as indicated by the TOPAR2, TOPAR4, and TOPAR6 scores and the SPID2, SPID4, and SPID6 scores (Table II, Figure 2). However, at shorter time points (eg, 30 minutes and 1 hour post-dose), the time periods when lidocaine plasma concentration was elevated (2 µg/mL; Figure 1b), the analgesic effect as assessed by TOPAR0.5 scores was significantly different from both placebo and active placebo (P .023), and TOPAR1 approached statistical significance (P .082). SPID0.5 and SPID1 scores were significantly different from placebo (P .041) but not active placebo (P .219; Table II). The analgesic effect of lidocaine was also evidenced by the peak analgesic effect; the peak pain relief scores were statistically significantly greater than that of placebo (P = .013) and active placebo (P = .029). The peak PID score was significantly greater than that of placebo (P = .006) but numerically greater than that of active placebo (Table II). The global scores for lidocaine at 2, 4, and 6 hours postdose were similar to those of placebo. Furthermore, there was no difference in duration of effect for lidocaine versus placebo, as assessed by the median time to rescue medication; median time to first dose of rescue medication was 1.6 hours for lidocaine versus 1.2 and 1.4 hours for placebo and active placebo, respectively.
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Oxycodone/Acetaminophen Versus Placebo
The study conduct was validated by oxycodone/acetaminophen providing statistically significantly better analgesic effect than placebo (P < .001), as assessed by TOPAR2, TOPAR4, and TOPAR6. Corresponding SPID2, SPID4, and SPID6; global evaluation at 2, 4 and 6 hours; the peak effect; and duration of effect were also significantly greater than placebo (Table II, Figure 2). Also, TOPAR0.5, TOPAR1, and SPID1 for oxycodone/acetaminophen were significantly greater than both placebo groups, whereas SPID0.5 was only significantly greater than placebo (Table II). Oxycodone/acetaminophen had a greater peak effect compared with both placebo groups (Table II). The analgesic effect for oxycodone/acetaminophen lasted longer than that of placebo: median time to rescue medication use for oxycodone/acetaminophen was 3.1 hours compared with 1.2 and 1.4 hours for placebo and active placebo, respectively.
Oxycodone/Acetaminophen Versus Lidocaine
The analgesic effect of oxycodone/acetaminophen was statistically significantly greater than lidocaine, as assessed by all predefined endpoints TOPAR2, TOPAR4, and TOPAR6 and SPID2, SPID4, and SPID6 (P .003), including peak effect (P < .05; Figure 2, Table II).
Tolerability
The percentage of subjects who reported clinical adverse experiences was similar in all treatment groups: 12 (60%) and 12 (60%) subjects, respectively, in the lidocaine and oxycodone/acetaminophen groups and 7 (70%) and 5 (50%) in the placebo and the active placebo groups, respectively. The most common adverse experiences were nausea, alveolitis, and headache (Table III).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Studies using the dental pain model have demonstrated efficacy of neuropathic pain drugs. For example, ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, at a low dose (0.3 mg/kg) and pregabalin (300 mg), with a mechanism of action that is not completely understood (believed to act via calcium channels and/or the NMDA receptor), have diminished postsurgery dental pain.10,11 These studies suggest that pain associated with the removal of impacted wisdom teeth may involve both inflammatory and neuropathic pain. To our knowledge, it has not been demonstrated that an Na-channel blocker (eg, lidocaine, mexiletine, or amitryptylline, drugs with efficacy in neuropathic pain) would affect postdental surgery pain.
To assess the relevance of dental impaction pain as a model to evaluate treatments for neuropathic pain, we performed a randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy of intravenous lidocaine in subjects with postsurgery dental pain with the objective to evaluate this standardized pain model as a potential pain model for neuropathic pain. The study showed that lidocaine can provide a modest degree of pain relief to subjects experiencing postsurgery dental pain over the first hour postdose, suggesting that the dental impaction model may be a relevant model for assessing efficacy of neuropathic pain medications, particularly if overall efficacy greater than that of lidocaine is expected.
The observed pain relief with intravenous lidocaine was modest. The most likely reason is that the portion of neuropathic pain in postsurgery dental pain is comparatively smaller than that observed in other conditions such as diabetic neuropathy and postherpetic neuralgia; however, it is conceivable that the lidocaine dose used was not sufficiently high. The lidocaine dose range and plasma concentration in this study were within approved and recommended dose range and the plasma concentration. Data from published studies show that lidocaine at doses of 1.5 to 5.0 mg/kg is effective in the treatment of various neuropathic pain conditions (eg, postamputation pain, diabetic neuropathy, and postherpetic neuralgia).4-6,8,12 Various doses and dosing regimens (eg, bolus followed by continuous infusion or continuous infusion alone) have been used. Intravenous lidocaine administered as 3 mg/kg over 3 minutes followed by a continuous infusion of 4 mg/kg over 60 minutes was effective in reducing neuropathic pain, including thalamic pain, trigeminal neuralgia, and phantom limb pain.5 Other studies showed that an infusion of 2 mg/mL over 60 minutes, resulting in mean serum concentrations of 2.4 µg/mL, decreased neuropathic pain.7,13 Lidocaine, administered as a 1-mg/kg bolus followed by a 4-mg/kg infusion (plasma levels of 2.1 ± 1.5 µg/mL), demonstrated efficacy in the treatment of postamputation pain5. Intravenous lidocaine at 5 mg/kg over 3 hours provided efficacy in patients with sciatica.13 It is not evident from the present study results whether higher lidocaine plasma concentrations would have provided a better response; however, 3 subjects in the lidocaine-treated group experienced tinnitus, suggesting that lidocaine exposure was adequate. Therefore, increasing lidocaine exposure may not be a feasible option in further testing this mechanism in the dental pain model, although other drugs (eg, gabapentin) may be useful. Nonetheless, the results showed that lidocaine could diminish the pain to a degree consistent with a small portion of the pain experienced after the extraction of impacted third molars for neuropathic pain. It is evident that the effect occurred early and during the time when the plasma concentration was elevated (2 µg/mL), that is, during the first hour. Therefore, if the primary endpoint had been prespecified as TOPAR0.5 or TOPAR1, the study would have demonstrated a treatment effect that was significantly different from placebo.
In summary, this randomized, double-blind study demonstrated that intravenous lidocaine diminished a portion of the pain experienced after extraction of impacted third molars during the first hour after patients received lidocaine. In addition, an opioid-combination drug provided superior pain relief compared with the 2 placebo groups and was also superior to lidocaine. The present study and the studies using ketamine10 and pregabalin11 suggest that pain associated with the removal of impacted wisdom teeth may involve both inflammatory and neuropathic pain. These studies have demonstrated that agents that act via Na- and/or Ca-channels, and/or NMDA receptors can modify pain associated with extraction of impacted third molars. The results of the present study provide additional evidence that an Na-channel blocker (lidocaine) modifies pain from the extraction of impacted third molars to a modest degree, although further studies with higher doses of lidocaine are needed to more completely assess the use of this model for neuropathic pain. Anticonvulsants other than pregabalin and tricyclics have also demonstrated efficacy in neuropathic pain; however, to our knowledge, they have not been tested using the dental impaction model. Studies using these agents would further substantiate the use of the dental impaction pain model in the evaluation of neuropathic pain.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Kawamata M, Tahahashi T, Kozuka Y, et al. Experimental incision-induced pain in human skin: effect of systemic lidocaine on flare formation and hyperalgesia. Pain. 2002;100: 77-89.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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13. Medrick-Goldberg T, Lifschitz D, Pud D, Adler R, Eisenberg E. Intravenous lidocaine, amantadine, and placebo in the treatment of sciatica: a double-blind, randomized, controlled study. Regional Anesth Pain Med. 1999;24: 534-540.[CrossRef]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), oxycodone/acetaminophen 10/650 mg (n = 20; = 
=), placebo (saline; n = 10; 
), or active placebo (diphenhydramine 50 mg; n = 10; 
).