Depot preparations of local anesthetics are designed to reduce the rate of systemic uptake from the site of drug administration, to remain longer at the site of injection, and to release drug slowly over time.1,2 The benefits of depot local anesthetics include a prolonged local anesthetic effect,3 a reduction of the plasma peak drug concentration,4 and the safe administration of larger doses,4 which further prolongs the duration of analgesia. Together with other investigators, we have previously reported animal5,6 and human7,8 pharmacokinetic and pharmacodynamic data for a liposomal bupivacaine preparation based on large multivesicular vesicles, with a high drug-to-phospholipid ratio. However, the clinical applicability of such liposomal bupivacaine preparations is typically limited by complicated pharmaceutical liposome preparation and drug loading and a short liposomal shelf half-life, even under refridgeration.8 In an accompanying article, we describe the simple preparation of a novel proliposomal ropivacaine oil with a shelf-stability of at least 2 years at room temperature.9 The proliposomal preparation is entirely homogenous ex vivo but undergoes transformation to multilamellar liposomal vesicles on exposure to the aqueous media. In that preclinical study, we report a prolonged sensory anesthetic effect in a surgical incision model in pigs; we also observed a pharmacokinetic profile typical for liposomal local anesthetics (T max was delayed and C max was below the toxic threshold, despite a proliposomal ropivacaine dose 8 times the toxic dose for plain ropivacaine, and the wound ropivacaine concentration at 4 days was almost 250 times greater than for the plain ropivacaine control).9
In this study, we report pharmacokinetic and pharmacodynamic data for the proliposomal ropivacaine preparation in volunteers. The aim of the human pharmacodynamic study was to examine whether subcutaneous administration of proliposomal ropivacaine demonstrated sustained local anesthetic effect at the site of injection when compared with plain ropivacaine and with vehicle control. The aim of the human pharmacokinetic study was to assess the plasma ropivacaine pharmacokinetics, after subcutaneous administration of proliposomal ropivacaine, when compared with a plain ropivacaine control containing one-eighth of the dose.
Both the pharmacodynamic and the pharmacokinetic studies were approved for volunteers by the IRB of Hadassah Hospital (0171-09-HMO) and by the Israel Ministry of Health (1078/2057). Written informed consent was obtained from all volunteers. The study was registered in the clinical trial registry of the National Library of Medicine, National Institute of Health (NCT00883194). Proliposomal ropivacaine (PRF-110) is an investigational drug (Israel Ministry of Health, IND 20090193).
All subjects were assessed for medical history and physical examination and had screening investigations including a resting 12-lead electrocardiogram (ECG), serum biochemistry, and complete blood count and urinalysis. Subjects were eligible for enrolment if they were 18 to 45 years old, male, American Society of Anesthesiologists physical status I, nonsmokers, within ±10% of ideal body weight (according to Metropolitan Life Insurance tablesa), had a negative urine toxicology screen (for cannabis, benzodiazepine, cocaine, morphine, oxycodone, amphetamine and tricyclic antidepressants), had not received any medications within 3 days (or 5 drug half-lives) of the start of the studies, and not taken any alcohol for 24 hours before the study. The exclusion criteria were as follows: (a) history of any significant hepatic, renal, endocrine, cardiac, neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic disorders; (b) hypersensitivity to any local anesthetic; and (c) abnormal screening ECG, including PR > 200 ms, QRS > 110 ms, QTcF > 400 ms, or lead II T wave abnormalities. All subjects had training with experimental sensory assessments at the time of enrolment, several days before baseline.
Preparation of Study Drugs
The study drug proliposomal ropivacaine (PRF-110) and the vehicle were prepared by Nextar ChemPharma Ltd. (Ness Ziona, Israel). The composition of proliposomal 4% ropivacaine was ropivacaine HCl base 4.78% (w/w), PL90G 53.91% (w/w), castor oil 35.21% (w/w), cysteine hydrochloride 0.10% (w/w), and ethanol 6.0% (w/w). Drugs were prepared as previously described.9 Terminal sterilization of the study drug was performed by moist–heat sterilization at 123oC (Fedegari Autoclave, PI-086, Fedegari Autoclavi SpA, Albuzzano, Italy). Plain 0.5% ropivacaine is commercially available and was manufactured by AstraZeneca AB (Södertälje, Sweden).
Pharmacodynamic Study Protocol
We designed a randomized, double-blind study to compare the local anesthetic effect of active and inactive control treatments. Study drug was 2.5 mL 4% (100 mg) proliposomal ropivacaine oil (PRF-110); active control was 2.5 mL plain 0.5% (12.5 mg) ropivacaine; inactive control was the proliposomal vehicle. All drugs were administered as subcutaneous injections, applied through a 5-mL luer-lock syringe using an 18-gauge needle. All subjects had 4 separate circumscribed 5-cm diameter circles drawn in indelible marker on their lower back, marked as areas 1, 2, 3, and 4. Each of the 3 drugs was injected subcutaneously into the center of a different, randomly assigned area, whereas the fourth randomly selected area was used as an unblinded, noninjected control site. Both treatment assignments and the order of assessment of each injected area were determined by computer-generated randomization. Both volunteers and observers recording pharmacodynamic end points were blinded to injection site and study drug allocation. Concealed allocation was by means of consecutive, opaque, sealed, and numbered envelopes, corresponding to the numbered drug vials. Drugs were prepared and labeled by the study pharmacologist and were injected by either EMD or YG. As the viscosity of the study drug and vehicle were noticeably different from plain ropivacaine, we ensured that the observers recording pharmacodynamic end points were removed from the room during drug administration.
There were 15 volunteers in the pharmacodynamic study and 9 separate volunteers in the pharmacokinetic study. Demographic data are presented in Table 1; there were no differences between study groups.
As this was the first human study of this formulation, we performed a single, unblinded interim analysis of safety and efficacy after the treatment of the first 3 subjects, after which an additional 12 subjects would be studied, as a typical sample size for experimental pain studies.
The effect of local analgesia induced by the study medication and controls were assessed by pinprick test (PPT) and experimental heat pain tolerance. PPT was assessed at the following time points: baseline and 0.5, 1, 2, 3, 4, 6, 7, 8, 10, 12, 14, 22, 24, 26, 29, 32, 34, 36, 38, 42, 48, and approximately 72 hours after drug administration. Experimental heat pain tolerance was assessed at baseline and at 2, 4, 6, 8, 10, 12, 14, 22, 24, 26, 29, 32, 34, 36, 38, 42, 48, and approximately 72 hours after drug administration. At time points that included testing both sensory modalities, PPT was performed before experimental heat pain tolerance. The first 48 hours of the study were conducted within the hospital premises. After 48 hours, and if there were no safety concerns, subjects were discharged home. They returned to the pain clinic 72 hours after drug administration for a local anesthetic efficacy and safety evaluation (see below) and on days 7 and 14 for a safety evaluation. If 1 or more of the efficacy parameters did not return to baseline at 72 hours postdrug administration, the study protocol would require that subject to undergo daily evaluations in person until the effect returned to baseline. There was a final phone follow-up on day 21 after the drug administration.
The PPT stimulus was a 90-mm, 26-gauge spinal needle that was held by its hub and pressed perpendicular to the skin until the needle bowed slightly. We assessed 3 numbered, randomized, blinded study areas and 1 open control reference area. At each observation area/time point, a PPT was performed first at the control reference area and then at one of the injected test areas. The response was the perceived pain to PPT, and the severity was referenced to the unblinded, noninjected, control area. Potential responses were “less painful” or “no sensation” (indicating anesthesia), “similar” (indicating no anesthesia), and “more painful” (indicating hyperalgesia). Paired PPTs were repeated 3 times for each injected test area; the first was used as a training stimulus and was not used for analysis, in keeping with standard psychophysical protocols.10 If there was a difference between the second and third PPT, the report of greater pain perception at the test site was used. Thus, a single report of “similar” indicated no local anesthetic effect at that area at that time point, even if there was also a single report of “less painful.” Local anesthetic regression at that test area had to be confirmed by another report of “similar” in the same area at the next consecutive data time point, in which case the time to local anesthetic regression was defined by the first data time point that indicated no local anesthetic effect and not by the second confirmatory time point. The process was repeated at each time point for all 3 injected test areas with respect to the control area.
Experimental Heat Pain Tolerance
Experimental heat pain was assessed using heat pain tolerance rather than heat pain threshold, because heat pain tolerance provides a better signal-to-noise ratio,10 is a more sensitive measure to detect drug-induced analgesia,10 and is clinically more relevant. Quantitative sensory testing was performed using a thermal sensory analyzer (TSA 2001, Medoc Advanced Medical Systems, Ramat Yishai, Israel), with a hand-held 5 × 5-mm thermode to administer nociceptive heat stimuli at the drug injection and control test sites. The thermode was applied to the skin, and the thermode temperature was equilibrated at 35°C for 5 seconds before heat pain testing. The thermode temperature was then increased at a rate of 1°C per second. The maximum thermode temperature was set at 50°C to avoid thermal injury. Study participants were asked to press the handset button (and to remove the thermode) as soon as the heat pain became intolerable; the corresponding thermode temperature was recorded. This procedure was performed 4 times, and the median of the final 3 measurements was recorded as the heat pain tolerance. The interval between the noxious heat stimuli was 30 seconds. Normalized heat pain tolerance for each test area was calculated as the change in heat pain tolerance with respect to baseline minus the change in heat pain tolerance in the control (uninjected) area. The area under the normalized heat pain tolerance versus time curve (AUC) was determined. The AUC between any 2 data points was calculated by using linear interpolation (or the trapezoid rule) as determined by the following formula: AUC = (E1 + E2)/2 × (T2−T1), where E1 and E2 are the effect measures (difference in heat pain tolerance from baseline) at successive data time points and T1 and T2 are the times from initial drug administration. The total AUC was determined by the sum of all the component AUCs.
Pharmacokinetic Study Protocol
We designed a prospective, open-label, controlled study to compare the pharmacokinetic characteristics of subcutaneously administered 4% proliposomal ropivacaine (PRF-110) compared with an active control (0.5% plain ropivacaine). Nine volunteers were randomly assigned to receive a single dose of either the study drug (4% proliposomal ropivacaine, 100 mg; n = 6) or the active control (0.5% plain ropivacaine, 12.5 mg; n = 3). Drug was injected subcutaneously as a 2.5-mL injection into the lower back as described earlier. For the first hour after drug administration, subjects were continuously monitored (3-lead ECG and noninvasive blood pressure). Other safety assessments were repeated as described earlier for the pharmacodynamic study.
Plasma Ropivacaine Concentration
After drug administration, blood was sampled to determine the plasma ropivacaine concentration at baseline immediately before drug administration and at 0.5, 1, 1.5, 2, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 72 hours in all subjects. Venous blood was aspirated from a 16-gauge forearm IV catheter after the aspiration of 10 mL of dead space and collected into the cooled EDTA vials. The vials were gently vortexed to ensure that all blood came into contact with the vial wall. Samples were immediately placed on ice and centrifuged (2000 revolutions per minute at 4°C) within 15 minutes of sampling. Plasma was separated, and samples of 2 mL plasma were labeled and stored at −70°C. Ropivacaine was extracted from plasma samples and analyzed using high-performance liquid chromatography, as previously described.9
Individual plasma concentration-time data obtained in the study were analyzed using a noncompartmental approach. The following pharmacokinetic parameters were calculated: primary end point: peak plasma ropivacaine concentration (C max); and secondary end points: the time to achieve the maximum plasma concentration (T max), the area under the ropivacaine concentration-time curve extrapolated to infinity (AUC), and the terminal half-life. Absolute ropivacaine bioavailability after subcutaneous administration was calculated using previously published concentration-time data after IV ropivacaine administration (Appendix 1).11 Pharmacokinetic analysis was performed using WinNonlin software (WinNonlin Version 4.5, Pharsight Corporation, Mountain View, CA).
The injection site was evaluated at baseline and at 0.5, 1, 2, 7, 24, 26, 36, 48, and approximately 72 hours. There was a phone safety follow-up on day 21 after the drug administration. Resting ECG was included in the safety assessments at baseline and at 1, 3, 8, and 48 hours after drug administration. A master randomization code was kept by both the sponsor and at the study site. The study site master code had individually sealed envelopes identifying the drug in each vial for each of the 15 subjects. The treatment for an individual subject could be unblinded in the event of an emergency, without breaking the code for any other subject.
Data were presented as mean (±SE). Primary pharmacodynamic end points (duration of sensory anesthesia to pinprick and AUC of normalized heat pain tolerance) were compared between proliposomal ropivacaine and plain ropivacaine using paired t tests (mean difference, 95% confidence interval [CI], and P value). Significance was assumed at P ≤ 0.01.
All subjects completed the study as planned.
The sensory anesthesia data to PPT are presented in Figure 1. The mean ± SE anesthesia duration for proliposomal ropivacaine and plain ropivacaine were 28.8 ± 6.0 hours and 15.9 ± 3.5 hours, respectively. The mean difference between groups was 16.8 hours (95% CI, 10.0–23.7; P = 0.001). The experimental heat pain tolerance data are presented in Figure 2. The mean ± SE AUC of the normalized heat pain tolerance over time was 55.0 ± 28.8 Δ°C·min for proliposomal ropivacaine and 9.6 ± 26.0 Δ°C·min for plain ropivacaine. The mean difference between groups was 64.6 Δ°C·min (95% CI, 10.2–119.0; P = 0.036).
The plasma ropivacaine data for the 2 study groups are presented in Table 2 and Figure 3. There was no significant difference in C max for proliposomal ropivacaine (164 ± 43 ng/mL; 99% CI, 119–210 ng/mL) compared with plain ropivacaine (100 ± 41 ng/mL; 99% CI, 39–162 ng/mL; P = 0.07), despite an 8-fold increase in drug dose in the proliposomal preparation. The 99% upper prediction limit for peak plasma concentrations (proliposomal ropivacaine, 351 ng/mL; plain ropivacaine, 279 ng/mL) were well below the putative toxic plasma concentration (600 ng/mL)12 for both groups.
There was an approximately 18-fold prolongation of the T max (15 ± 11 hours) for proliposomal ropivacaine when compared with plain ropivacaine (0.83 ± 0.29 hours; P = 0.0031). Similarly there was a significant increase in the terminal half-life (13.8 ± 3.6 hours vs 5.9 ± 2.3 hours; P = 0.011) and the AUC (5090 ± 1476 h·ng/mL vs 593 ± 168 h·ng/mL; P = 0.0014).
All treatments were well tolerated. Local anesthetic effects underwent regression within 72 hours in all patients; there were no major adverse events, and the study code was not broken in any patient.
In an accompanying preclinical study we show that, on exposure to the aqueous tissue models (saline and plasma), the homogenous proliposomal ropivacaine-loaded oil undergoes nanoparticular heterogeneity with the creation of multiple large multivesicular vesicles.9 In that study, we presented data that demonstrated that proliposomal ropivacaine exhibited pharmacodynamic and pharmacokinetic characteristics typical of liposomal local anesthetics with a prolonged local anesthetic effect, delayed systemic redistribution, and a low C max relative to the dose administered. In this study, we present pharmacodynamic and pharmacokinetic data demonstrating the same phenomena in healthy volunteers. There was a marked prolongation of sensory anesthesia to both pinprick and experimental heat pain, no significant difference in C max (despite an 8-fold increase in drug dose in the proliposomal preparation), and a significant increase of the T max, terminal half-life, and AUC, typical for liposomal or depot preparations.
Our pharmacodynamic and pharmacokinetic data appear similar to our animal data and also to the pharmacodynamic/pharmacokinetic data previously reported for other liposomal local anesthetics.4,7 At first appearance, drug bioavailability in excess of 100% as reported in our study may seem surprising; however, this is likely to be related to methodologic differences between our study and the published study11 used as our IV reference. These differences include the use of a different ropivacaine assay and higher plasma ropivacaine concentrations over a shorter duration in the IV study. In addition, comparison of the AUC values for calculation of the bioavailability assumes that drug clearance was identical for these different modes of administration; however, the validity of this assumption may be undermined if nanoparticles are absorbed intact into the systemic circulation, leading to altered systemic distribution and elimination.4
These animal9 and human studies reporting that a homogenous proliposomal oil loaded with ropivacaine elicits a pharmacologic response identical to that of a liposomal preparation are important, given the ease of preparation and extended shelf-stability at room temperature of the study drug. The liposomal multivesicular vesicles administered in previous studies4,7 required the manufacture of multivesicular liposomes, and active remote drug loading along a transliposome ammonium sulfate gradient was limited by drug leakage from liposomes and was stable for only 30 days. By contrast, this proliposomal drug is prepared, stored, and injected as an oil, and it produces multivesicular liposomes only on contact with aqueous media. As a consequence, the drug has a greatly extended shelf-stability (at least 2 years at room temperature). In the accompanying preclinical study, we discuss the theoretical factors affecting controlled drug release in liposomal local anesthetics, including drug leakage from liposomes before administration, drug leakage from liposomes before reaching their site of action, and predictable slow release at the intended site of action. In this study, none of the proliposomal drug is liposome-bound before administration, and all drugs were administered directly to the subcutaneous site of action. However, despite the encouraging pharmacodynamic and pharmacokinetic data in both animals and humans, little is understood about the factors that control drug release from the liposomes in this preparation.
Only a few clinical studies have reported the use of perineural or neuraxial liposomal local anesthetic administration,13–15 and adequate preclinical studies demonstrating the lack of neurotoxicity have not yet been reported; consequently liposomal local anesthetics do not meet consensus criteria for the use of investigational neuraxial drugs.16 Accordingly, the clinical utility of liposomal local anesthetics has currently been limited to wound infiltration in peripheral surgery; bunionectomy,17 hemorrhoidectomy,18 breast augmentation,19 and knee arthroplasty.20 Although previously, only bunionectomy and hemorrhoidectomy were Food and Drug Administration-approved applications for the commercially available liposomal bupivacaine, this limitation was revised in December 2015.b In these studies, liposomal local anesthetics have provided prolonged analgesia without side effects or impaired wound healing.21 In these clinical scenarios, it would appear that proliposomal ropivacaine oil behaves exactly like a liposomal preparation, but its ease of preparation and extended shelf-life will likely confer an advantage over remote-loaded preprepared liposomal formulations.
In this study, we administered only 100 mg proliposomal ropivacaine, less than half the maximum allowable plain ropivacaine dose (3 mg/kg).22 However, the observed reduction of C max should allow the safe administration of larger doses, further prolonging the duration of analgesia. Further studies will need to be performed to define the maximum allowable proliposomal ropivacaine dose. Additional future studies may include: (1) pharmacodynamic studies using this higher dose, which is likely to provide prolonged sensory anesthesia of longer duration than the effect observed in this study; (2) comparative pharmacokinetic/pharmacodynamic studies comparing the proliposomal study drug with existing liposomal local anesthetic preparations; (3) assessment of potential neurotoxicity in animals after perineural or neuraxial administration before studies of perineural and neuraxial drug administration in patients.
Finally, it should be noted that this study was performed in men only. In this proof-of-concept study, the principle aim was to assess whether the study drug exhibited pharmacodynamic and pharmacokinetic evidence of liposomal behavior. The previous pharmacodynamic7 and pharmacokinetic4 studies in liposomal bupivacaine to which we referred were performed in men only. Furthermore, the extension of this study to females at the proof-of-concept stage would likely have adversely affected signal-to-noise ratio, because women are more likely than men to suffer prior pain23 and there is a difference in experimental pain perception between men and women24 and within females at different stages of the menstrual cycle.25 Subsequent stages of clinical drug research and development will need to assess gender differences in pharmacokinetic and pharmacodynamic responses.
Subcutaneously administered proliposomal ropivacaine exerted prolonged anesthesia in volunteers with delayed elimination from the site of injection, typical for liposomal local anesthetics. The advantage of this novel proliposomal ropivacaine oil in comparison with preprepared liposomal local anesthetics is its ease of preparation and its extended shelf-stability (>2 years) at room temperature.
Noncompartmental analysis of the data was performed using individual plasma concentration-time profiles and doses normalized to subjects’ body weights. Because we did not evaluate the pharmacokinetics of IV ropivacaine in this study, and to assess the bioavailability of subcutaneous ropivacaine, the IV pharmacokinetic profile of plain ropivacaine was obtained from published data11 and data extracted by computer digitization (Supplemental Digital Content 1, Supplemental Fig. 1, http://links.lww.com/AA/B378). In that study, 0.6 mg/kg ropivacaine was administered as a 30-minute IV infusion, and the terminal half-life of IV ropivacaine was 3.2 hours. The IV plain ropivacaine data were adequately described using a 2-compartment model with linear elimination. The volume of the central compartment was estimated to be 511 mL/kg, the elimination rate constant was 0.657/h, and the rate constants for transfer from the central and from the peripheral compartments were 0.619/h and 0.495/h, respectively. The area under the concentration-time profile after IV infusion served as the basis for the calculation of the bioavailability for subcutaneous ropivacaine in our study. The data indicate that plain ropivacaine was completely absorbed after subcutaneous injection in our study.
To more thoroughly investigate the absorption kinetics of plain ropivacaine after subcutaneous administration, deconvolution was performed using the mean concentration-time profile of plain ropivacaine after subcutaneous injection. The pharmacokinetic parameters of IV ropivacaine (see above) were used to describe the unit response function. More than 60% of the dose was absorbed during the first 2 hours (Supplemental Digital Content 2, Supplementary Fig. 2, http://links.lww.com/AA/B379). We evaluated several absorption models for describing the absorption behavior of ropivacaine after subcutaneous administration. In these models, the systemic distribution and elimination parameters were fixed to the previously estimated values for IV ropivacaine; only parameters describing the absorption process were evaluated. The final model, shown in Figure 4, included 2 sequential absorption compartments (kt [transit rate constant]) with first-order absorption rates ka1 and ka2. As shown in Figure 5, this model provided a good description of the experimental data, and parameters were estimated with reasonable precision: kt = 1.88/h (% CV 82), ka1 = 1.14 (% CV 74), and ka2 = 0.0714 (% CV 23).
A theoretical absorption model for the proliposomal ropivacaine formulation could be proposed similar to our previous theoretical absorption model for liposomal bupivacaine.4 However, because of the complex (probably biphasic) release profile for proliposomal ropivacaine at the subcutaneous environment and the unknown systemic distribution behavior, we cannot estimate the parameters of such a model with sufficient precision. Several pharmacodynamic models were evaluated to attempt to describe the relationship between the amount of ropivacaine at the subcutaneous compartment and the local anesthetic effect (including simple direct effect, or Emax, model, and a biphasic model). Mean normalized heat pain tolerance was used as the response variable. However, given the high interindividual variability in pharmacodynamic response, neither of these models could provide a satisfactory fit of the pharmacodynamic–pharmacokinetic profile.
Name: Yehuda Ginosar, BSc, MBBS.
Contribution: This author assisted with study design, performed the statistical analysis of the pharmacodynamic data, and drafted the final manuscript.
Attestation: Yehuda Ginosar attests to the integrity of the analysis reported in this manuscript.
Conflicts of Interest: Yehuda Ginosar together with Elyad M. Davidson received a research grant ($10,000) from Painreform Ltd., through Hadassit Inc., Hadassah Hebrew University Medical Center, which was used to support volunteer and investigator costs. He has no other relationship with Painreform Ltd.
Name: Simon Haroutounian, PhD.
Contribution: This author with Leonid Kagan was responsible for pharmacokinetic analysis.
Attestation: Simon Haroutounian attests to having approved the final manuscript.
Conflicts of Interest: Simon Haroutounian declares no conflicts of interest.
Name: Leonid Kagan, PhD.
Contribution: This author together with Simon Haroutounian was responsible for pharmacokinetic analysis.
Attestation: Leonid Kagan attests to having approved the final manuscript.
Conflicts of Interest: Leonid Kagan declares no conflicts of interest.
Name: Michael Naveh, Dr. Med Vet.
Contribution: As COO of Painreform Ltd., this author was the initiator and sponsor for the overall execution of the study.
Attestation: Michael Naveh attests to having approved the final manuscript.
Conflicts of Interest: Michael Naveh is an employee of Painreform Ltd., who hold patent rights to proliposomal ropivacaine (PRF-110) and its proliposomal platform.
Name: Arnon Aharon, MD.
Contribution: This author contributed to the study design, was the monitor for data collection, and was the archival author responsible for maintaining the study records.
Attestation: Arnon Aharon attests to the integrity of the original data and is the archival author responsible for maintaining the study records; he attests to approving the final manuscript.
Conflicts of Interest: Arnon Aharon was at the time of the study a clinical studies consultant to Painreform Ltd., who hold patent rights to proliposomal ropivacaine (PRF-110) and its proliposomal platform.
Name: Elyad M. Davidson, MD.
Contribution: This author assisted with study design, conduct of the study, and data collection.
Attestation: Elyad M. Davidson attests to the integrity of the analysis reported in this manuscript. He attests to having approved the final manuscript.
Conflicts of Interest: Elyad M. Davidson together with Yehuda Ginosar received a research grant ($10,000) from Pain Reform Ltd., Tel Aviv, through Hadassit Inc., Hadassah Hebrew University Medical Center, which was used to support volunteer and investigator costs in the clinical study. He has no other relationship with Pain Reform Ltd.
This manuscript was handled by: Terese T. Horlocker, MD.
b http://www.anesthesiologynews.com/ViewArticle.aspx?d=Web%2BExclusives&d_id=175&i=December+2015&i_id=1256&a_id=34581; http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/enforcementactivitiesbyfda/warninglettersandnoticeofviolationletterstopharmaceuticalcompanies/ucm477250.pdf.
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