[ROUTES OF MEDICAL CANNABIS ADMINISTRATION- IS SMOKING THE PREFERRED ROUTE?]

INTRODUCTION: The number of medical cannabis licenses in Israel is increasing persistently (over 120,000 approved licenses in October 2022), reaching about 1.5% of adult population. Medical cannabis products are available in two main forms: inflorescence (administered by smoking or evaporation) and cannabis oil (administered sub-lingually). Data from the Israel ministry of health, regarding the split between these forms, show a major preference for inflorescence products over cannabis oils. This preference is increasing over time. This article reviews the main differences between the administration of these forms and their effects on the quality of treatment. It's conclusion is that for the most common cases of cannabis treatment, sublingual oils should be preferred and that the medical community has an important role in driving this change.

Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.

The cannabis plant exerts its pharmaceutical activity primarily by the binding of cannabinoids to two G protein-coupled cannabinoid receptors, CB1 and CB2. The role that cannabis terpenes play in this activation has been considered and debated repeatedly, based on only limited experimental results. In the current study we used a controlled in-vitro heterologous expression system to quantify the activation of CB1 receptors by sixteen cannabis terpenes individually, by tetrahydrocannabinol (THC) alone and by THC-terpenes mixtures. The results demonstrate that all terpenes, when tested individually, activate CB1 receptors, at about 10-50% of the activation by THC alone. The combination of some of these terpenes with THC significantly increases the activity of the CB1 receptor, compared to THC alone. In some cases, several fold. Importantly, this amplification is evident at terpene to THC ratios similar to those in the cannabis plant, which reflect very low terpene concentrations. For some terpenes, the activation obtained by THC- terpene mixtures is notably greater than the sum of the activations by the individual components, suggesting a synergistic effect. Our results strongly support a modulatory effect of some of the terpenes on the interaction between THC and the CB1 receptor. As the most effective terpenes are not necessarily the most abundant ones in the cannabis plant, reaching "whole plant" or "full spectrum" composition is not necessarily an advantage. For enhanced therapeutic effects, desired compositions are attainable by enriching extracts with selected terpenes. These compositions adjust the treatment for various desired medicinal and personal needs.

Vapor Pressure, Vaping, and Corrections to Misconceptions Related to Medical Cannabis' Active Pharmaceutical Ingredients' Physical Properties and Compositions.

Medical cannabis products contain dozens of active pharmaceutical ingredients (APIs) derived from the cannabis plant. However, their actual compositions and relative doses significantly change according to the production methods. Product compositions are strongly dependent on processing step conditions and on components' evaporation during those steps. Review of the documentation presented to caregivers and to patients show erroneous data or misinterpretation of data related to the evaporation, for example, cannabinoids' boiling points, as well as confusions between terms, such as boiling, vaporization, and evaporation. Clarifying these aspects is essential for caregivers, for researchers, and for developers of manufacturing processes. Original and literature data were analyzed, comparing composition changes during various processing steps and correlating the extent of change to components' vapor pressures at the corresponding temperature. Evaporation-related composition changes start at temperatures as low as those of drying and curing and become extensive during decarboxylation. The relative rate of components' evaporation is determined by their relative vapor pressure and monoterpenes are lost first. On vaping, terpenes are inhaled before cannabinoids do. Commercial medical cannabis products are deficient in terpenes, mainly monoterpenes, compared with the cannabis plants used to produce them. Terms, such as "whole plant" and "full spectrum," are misleading since no product actually reflects the original cannabis plant composition. There are important implications for medical cannabis manufacturing and for the ability to make the most out of the terpene API contribution. Medical cannabis products' composition and product delivery are controlled by the relative vapor pressure of the various APIs. Quantitative data provided in this study can be used for improvement to reach better accuracy, reproducibility, and preferred medical cannabis compositions.

Terpene-Enriched CBD oil for treating autism-derived symptoms unresponsive to pure CBD: Case report.

Cannabidiol (CBD) rich products are successfully used in some countries for treating symptoms associated with autism spectrum disorder (ASD). Yet, CBD provides insufficient intervention in some individuals, or for some characterizing symptoms of ASD, raising the need for improved compositions. The current study presents a case wherein pure CBD was sufficient for treating ASD during childhood and early adolescence. However, it became insufficient during puberty accompanied by increased hyperactivity, agitation, and frequent severe aggressive behavior. Increasing the CBD dose did not result in significant improvement. Enriching the pure CBD with a carefully selected blend of anxiolytic and calming terpenes, resulted in gradual elimination of those aggressive events. Importantly, this was achieved with a significantly reduced CBD dose, being less than one-half the amount used when treating with pure CBD. This case demonstrates a strong improvement in efficacy due to terpene enrichment, where pure CBD was not sufficient. Combined with terpenes' high safety index and the ease with which they can be incorporated into cannabinoid-containing products, terpene-enriched CBD products may provide a preferred approach for treating ASD and related conditions. The careful selection of terpenes to be added enables maximizing the efficacy and tailoring the composition to particular and changing needs of ASD subjects, e.g., at different times of the day (daytime vs nighttime products).

Optimal Treatment with Cannabis Extracts Formulations Is Gained via Knowledge of Their Terpene Content and via Enrichment with Specifically Selected Monoterpenes and Monoterpenoids.

Differences between therapeutic effects of medical cannabis inflorescences and those of their extracts are generally attributed to the differences in administration form and in the resultant pharmacokinetics. We hypothesized that difference may further extend to the composition of the actually consumed drug. Cannabinoid and terpene contents were compared between commercial cannabis inflorescences (n = 19) and decarboxylated extracts (n = 12), and between inflorescences and decarboxylated extracts produced from them (n = 10). While cannabinoid content was preserved in the extracts, a significant loss of terpenes was evident, mainly in the more volatile monoterpenes and monoterpenoids (representing a loss of about 90%). This loss changes the total terpene content, the proportion of monoterpenes out of the total terpenes, and the monoterpene/cannabinoid ratio. Terpene deficiency might impair extracts' pharmacological efficacy and might contribute to the patients' preference to inflorescences-smoking. This argues against the validity of terms such as "whole plant" and "full spectrum" extracts and creates a misleading assumption that extracts represent the pharmacological profile of the sourced inflorescences. Furthermore, it reduces the diversity in extracts, such as loss of differences between sativa-type and indica-type. Enriching cannabis extracts with selected terpenes may provide a suitable solution, generating a safe, precise, and reproducible drug with tailored cannabinoid and terpene contents. Careful selection of terpenes to be added enables tailor-made extracts, adjusted for various medicinal aims and for different populations.

Anesthetic considerations in medical cannabis patients.

PURPOSE OF REVIEW: Growing numbers of patients, consuming cannabinoids admitted to surgery, create a challenge to anesthesia providers. This review provides a summary of recent literature related to cannabis and anesthesia, with specific recommendations to the anesthetic management of medical cannabis consumers. RECENT FINDINGS: At present, cannabis has found its way to public consensus in many countries and is penetrating slower to different medical fields. We relate and discuss recent findings investigating effects of cannabis consumption on the various aspects including perioperative measures, post-operative pain, PONV, cardiovascular stability, and anesthesia monitoring. SUMMARY: Recent surveys estimate that 10-20% of adult populations have consumed cannabis in the past year. Medical cannabis consumers are a newer group of cannabis users. Anesthesia providers have to update their knowledge on cannabis and possible anesthetic interaction. It is unreasonable to make recommendations that apply to the whole heterogeneous group of cannabis users, but is easier with the more homogenous group of Medical cannabis users, characterized by frequent use and relatively high cannabis doses, combined with good knowledge of administered composition and protocol, as well as adverse and withdrawal effects. Anesthesia providers have to know the effects and modify anesthetic plan accordingly. We provide perioperative anesthetic recommendations related to medical cannabis consumers. Collecting information of the effects of medical cannabis use in perioperative setting will further create a highly useful database for anesthetics in the close future.

A Novel Proliposomal Ropivacaine Oil: Pharmacokinetic-Pharmacodynamic Studies After Subcutaneous Administration in Pigs.

BACKGROUND: Liposomal local anesthetics are limited by a short liposomal shelf-life, even when under refrigeration. We describe a novel proliposomal ropivacaine that produces liposomes in situ, only after exposure to aqueous media. METHODS: In vitro: Nanoparticles were assessed (particle size distribution analyzer, cryo-transmission electron microscopy) at baseline and after exposure to saline/plasma. TOXICITY: In porcine wound healing study (n = 12), healing was assessed by photography, clinical assessment, and histology. Pharmacodynamics: Seventeen young piglets were randomly assigned to plain 0.5% ropivacaine (n = 5), proliposomal 4% ropivacaine (n = 6), or sham (n = 6). Tactile threshold was assessed using von Frey filaments applied to the surgical wound; the nonoperated skin was used as a control. Tactile threshold over time was determined using area under the curve (AUC) and assessed by 1-way analysis of variance. PHARMACOKINETICS: 8 young piglets were randomly assigned to plain 0.5% (25 mg, n = 4) or proliposomal 4% (200 mg, n = 4) ropivacaine. Plasma ropivacaine was assessed by high-performance liquid chromatography at baseline and at intervals over 36 hours. Paired ropivacaine concentration (from wound exudate and plasma) was obtained at 96 hours. Data were analyzed using noncompartmental and compartmental models. RESULTS: In vitro: On exposure to saline and plasma, the study drug was transformed from a homogenous oil to an emulsion containing liposomes of approximately 1.4-µm diameter; this effect was dilution dependent and stable over time. TOXICITY: All wounds healed well; no effect of drug group was observed. Pharmacodynamics: Plain and proliposomal ropivacaine provided sensory anesthesia for approximately 6 and 30 hours, respectively. There was an approximately 7-fold increase in the AUC of anesthesia for proliposomal ropivacaine compared with plain ropivacaine (mean difference, 1010; 95% confidence interval [CI], 625-1396 g·h/mm; P < 0.0001). PHARMACOKINETICS: There was no difference in Cmax (2.31 ± 0.74 vs 2.32 ± 0.46 mg/L), despite an approximately 8-fold difference in dose. However, proliposomal ropivacaine was associated with a marked prolongation of Tmax (6.50 ± 6.35 vs 0.5 ± 0.0 hours), terminal half-life (16.07 ± 5.38 vs 3.46 ± 0.88 hours; P = 0.0036), and ropivacaine-time AUC (47.72 ± 7.16 vs 6.36 ± 2.07 h·mg/L; P < 0.0001), when compared with plain ropivacaine. The proliposomal formulation provided an approximately 250-fold higher ropivacaine concentration in the surgical wound (mean difference, 3783 ng/mL; 95% CI, 1708-5858; P = 0.001) and an approximately 25-fold higher wound:plasma ropivacaine concentration ratio (mean difference, 126; 95% CI 38-213; P = 0.011). CONCLUSIONS: Proliposomal ropivacaine exerted prolonged anesthesia with delayed elimination, typical for liposomal drugs. The advantage of this novel proliposomal ropivacaine is its ease of preparation and its extended shelf-stability (>2 years) at room temperature.

Proliposomal Ropivacaine Oil: Pharmacokinetic and Pharmacodynamic Data After Subcutaneous Administration in Volunteers.

BACKGROUND: Slow-release liposomal formulations of local anesthetics prolong plasma redistribution and reduce peak plasma drug concentration, allowing safer administration of larger doses and further prolonging sensory effects. However, their clinical applicability is limited by expensive manufacture and liposomal leakage. Previously, we described the simple preparation of a novel proliposomal ropivacaine oil that produces multilamellar liposomal vesicles on exposure to aqueous media and that has a shelf-life of >2 years at room temperature. In this study, we present both pharmacodynamic and pharmacokinetic data in healthy volunteers after subcutaneous injection of this novel proliposomal preparation of ropivacaine. METHODS: In the pharmacodynamic phase of this study, 15 volunteers received 3 separate subcutaneous injections of 2.5 mL containing 1 of the following drugs: proliposomal 4% ropivacaine, plain 0.5% ropivacaine, and the ropivacaine-free proliposomal vehicle. Drugs were administered into the lower back, and their location was randomized and blinded; a separate area was used as an uninjected, open control. Experimental sensory assessment was made at repeated intervals over 72 hours using both pinprick sensation and experimental heat pain tolerance (assessed using quantitative sensory testing). In a separate pharmacokinetic phase of this study, 9 volunteers received subcutaneous injections of 2.5 mL of either proliposomal 4% ropivacaine (n = 6) or plain 0.5% ropivacaine (n = 3); these participants had plasma ropivacaine concentrations assessed at repeated intervals over 72 hours. RESULTS: The mean ± SE duration of pinprick anesthesia after proliposomal and plain ropivacaine administration lasted 28.8 ± 6.0 and 15.9 ± 3.5 hours, respectively (mean difference, 16.8 hours; 95% confidence interval, 10.0-23.7; P = 0.001). For experimental heat pain, the anesthesia duration was approximately 36 and 12 hours, respectively, with mean ± SE area under the curve of the normalized heat pain tolerance over time 55.0 ± 28.8 Δ°C·min for proliposomal ropivacaine and 9.6 ± 26.0 Δ°C·min for plain ropivacaine (mean difference, 64.6 Δ°C·min; 95% confidence interval, 10.2-119.0; P = 0.036). In the pharmacokinetic study, there was no significant difference in peak plasma concentration in the proliposomal ropivacaine group (164 ± 43 ng/mL compared with 100 ± 41 ng/mL in the plain ropivacaine group; P = 0.07) despite an 8-fold increase in ropivacaine dose in the proliposomal group. The 99% upper prediction limit for peak plasma concentrations (351 ng/mL proliposomal; 279 ng/mL plain) was well below the putative toxic plasma concentration for both groups. The mean ± SE terminal half-life and area under the curve for proliposomal ropivacaine versus plain ropivacaine were 13.8 ± 3.6 hours vs 5.9 ± 2.3 hours (P = 0.011) and 5090 ± 1476 h·ng/mL vs 593 ± 168 h·ng/mL (P = 0.0014), respectively. CONCLUSIONS: The prolonged pharmacodynamic effect of proliposomal ropivacaine, together with its delayed elimination and prolonged redistribution to plasma, is compatible to depot-related slow-release and similar to the performance of other liposomal local anesthetics. The advantage of the proliposomal oil is its ease of preparation and its extended shelf-stability at room temperature.

Performance of aseptic technique during neuraxial analgesia for labor before and after the publication of international guidelines on aseptic technique.

BACKGROUND: Aseptic technique and handwashing have been shown to be important factors in perioperative bacterial transmission, however compliance often remains low despite guidelines and educational programs. Infectious complications of neuraxial (epidural and spinal) anesthesia are severe but fortunately rare. We conducted a survey to assess aseptic technique practices for neuraxial anesthesia in Israel before and after publication of international guidelines (which focused on handwashing, jewelry/watch removal and the wearing of a mask and cap). METHODS: The sampling frame was the general anesthesiology workforce in hospitals selected from each of the four medical faculties in Israel. Data was collected anonymously over one week in each hospital in two periods: April 2006 and September 2009. Most anesthesiologists received the questionnaires at departmental staff meetings and filled them out during these meetings; additionally, a local investigator approached anesthesiologists not present at these staff meetings individually. Primary endpoint questions were: handwashing, removal of wristwatch/jewelry, wearing mask, wearing hat/cap, wearing sterile gown; answering options were: "always", "usually", "rarely" or "never". Primary endpoint for analysis: respondents who both always wash their hands and always wear a mask ("handwash-mask composite") - "always" versus "any other response". We used logistic regression to perform the analysis. Time (2006, 2009) and hospital were included in the analysis as fixed effects. RESULTS: 135/160 (in 2006) and 127/164 (in 2009) anesthesiologists responded to the surveys; response rate 84% and 77% respectively. Respondents constituted 23% of the national anesthesiologist workforce. The main outcome "handwash-mask composite" was significantly increased after guideline publication (33% vs 58%; p = 0.0003). In addition, significant increases were seen for handwashing (37% vs 63%; p = 0.0004), wearing of mask (61% vs 78%; p < 0.0001), hat/cap (53% vs 76%; p = 0.0011) and wearing sterile gown (32% vs 51%; p < 0.0001). An apparent improvement in aseptic technique from 2006 to 2009 is noted across all hospitals and all physician groups. CONCLUSION: Self-reported aseptic technique by Israeli anesthesiologists improved in the survey conducted after the publication of international guidelines. Although the before-after study design cannot prove a cause-effect relationship, it does show an association between the publication of international guidelines and significant improvement in self-reported aseptic technique.

High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans.

BACKGROUND: Depot formulations prolong the analgesic effect of local anesthetics and reduce peak plasma drug concentration. This allows for safer administration of larger doses of local anesthetics, which further prolongs the duration of analgesic effect. We previously reported the development of large multivesicular vesicles (LMVVs) remotely loaded with bupivacaine (LMVV liposomal bupivacaine) and demonstrated a >5-fold prolongation of analgesic effect in animals and humans. In this study, we present pharmacokinetic data of LMVV liposomal bupivacaine in humans. METHODS: Healthy volunteers received subcutaneous injections of 20 mL plain 0.5% bupivacaine and, 1 week later, 20 mL of 2% LMVV liposomal bupivacaine in a prospective, open-label, crossover, controlled study. RESULTS: Eight subjects were studied. No subjective side effects of local anesthetics were observed. The maximal plasma concentration and the time to achieve maximal plasma concentration were assessed by modeling plasma concentration-time profiles. Maximal plasma concentration was not significantly different between groups (0.87 +/- 0.45 microg/mL and 0.83 +/- 0.34 microg/mL for plain and liposomal bupivacaine, respectively; P = not significant, 0.83). These values are well below the putative toxic plasma concentration of 2 to 4 microg/mL. Time to achieve maximal plasma concentration was 7-fold greater for the liposomal preparation (262 +/- 149 minutes vs 37.5 +/- 16 minutes, P < 0.01). CONCLUSIONS: Peak plasma bupivacaine concentrations were not different in the 2 groups, despite a 4-fold increase in total bupivacaine dose administered in the novel liposomal preparation. The delayed elimination and prolonged redistribution of liposomal bupivacaine to plasma is compatible with the depot-related slow-release effect leading to the prolonged pharmacodynamic effect previously reported.

Magnetic resonance imaging findings after uneventful continuous infusion neuraxial analgesia: a prospective study to determine whether epidural infusion produces pathologic magnetic resonance imaging findings.

BACKGROUND: Magnetic resonance imaging (MRI) is considered the preferred diagnostic tool to determine whether postepidural neurologic symptoms are due to hematoma or abscess. However, there is currently no published information regarding the normal appearance of a MRI after a continuous epidural infusion. In this prospective cohort study, we defined the characteristic appearance of MRI findings after uneventful epidural analgesia. METHODS: Thirty women were prospectively enrolled to undergo a lumbar MRI after labor and delivery. The study group consisted of 15 women who received neuraxial analgesia with a combined spinal epidural technique followed by continuous epidural infusion, whereas the control group included 15 women who delivered without receiving neuraxial analgesia. All patients received a MRI within 12 h of delivery via a 1.5T scanner. MRIs were reviewed by two neuroradiologists who were blinded to the patient's study group allocation and asked to document the presence or absence of fluid collection, air collection, or soft tissue abnormalities. RESULTS: There were no radiologically significant fluid collections, hematomas, or mass effects noted on the thecal sac of any of the 30 MRI studies. A small amount of epidural air was seen in 77% of MRI studies after epidural analgesia, but there was no indention on the thecal sac. CONCLUSIONS: The lack of significant collections or mass effects seen in the MRIs of our patients after continuous infusion of epidural analgesia suggests that the presence of these findings in a patient with new neurologic symptoms after administration of epidural analgesia should be considered pathologic and warrant immediate attention.

Evaluation of magnetic resonance imaging following neuraxial steroid administration: does epidural injection produce pathologic findings?

BACKGROUND AND OBJECTIVES: Infection or hematoma following epidural anesthesia is a rare but potentially devastating complication unless diagnosed early. In order to diagnose spinal cord involvement, the currently recommended imaging test is magnetic resonance imaging (MRI). Despite this, no previous studies have been performed to define typical MRI findings following uneventful epidural injection. The purpose of this pilot study was to compare magnetic resonance images before and after epidural injection to define the characteristic appearance of MRI following an uneventful epidural steroid injection. METHODS: Ten patients were prospectively enrolled and received an MRI study before and after an epidural injection of steroids plus local anesthetic for chronic low back pain using a loss of resistance to air technique. The magnetic resonance images were reviewed by 2 neuroradiologists who were blinded as to whether the scan was performed before or after the epidural injection. RESULTS: Review of 20 MRI studies revealed no fluid collections, hematomas, or mass effect on the thecal sac. A needle track and a small amount of epidural air was seen in the majority of post-epidural scans, but did not cause indentation of the thecal sac in any patient. None of the findings observed by the radiologists in the post-epidural scans were considered clinically significant. CONCLUSIONS: The results of this pilot study demonstrated that after uneventful epidural injection in otherwise healthy patients, there were no new pathologic findings on MRI scans. Further MRI studies in large populations and in different clinical situations should be performed to confirm these preliminary findings.

Perioperative management of chronic pain patients with opioid dependency.

PURPOSE OF REVIEW: In this article, we discuss the perioperative anesthesia and pain management of patients with chronic pain receiving chronic opioid administration. In our practice we may expect to be confronted with opioid-dependent patients in routine anesthesia practice and should acquire specific knowledge and skills to effectively manage the perioperative and acute pain management issues that arise. RECENT FINDINGS: The number of patients treated chronically with opioids has increased steadily over the past decade; currently about 10% of all chronic-pain patients are treated with opioids. As these patients are no longer confined to terminally ill cancer patients, growing numbers of these patients are facing surgical interventions. SUMMARY: In our clinical practice, we should employ multimodal pain management therapy by using an around-the-clock regimen of nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, acetaminophen, and regional blockade. Dosing regimens should be individualized to optimize efficacy while minimizing the risk of adverse events.

Pain management and regional anaesthesia in the trauma patient.

PURPOSE OF THE REVIEW: Treatment of the trauma patient has evolved rapidly in the past decade. Nevertheless, the treatment of pain as part of overall trauma management has been relatively neglected. This update reviews recent publications related to pain relief in the trauma patient. RECENT FINDINGS: Although recent publications suggest that the assessment and treatment of pain in trauma have improved, most studies still document inadequate analgesia. We discuss the use of different analgesia strategies in the prehospital and emergency room settings. SUMMARY: Educating the emergency room staff to perform early routine assessment of pain and to be familiar with the administration of analgesia are key elements to improved pain management in trauma. Peripheral nerve block techniques should be practised by emergency room staff. If simple techniques are chosen, competence can be achieved with short, focused training sessions. Further developments are needed in order to provide safer and more effective analgesia to the trauma patient.

A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia.

BACKGROUND: Currently available local anesthetics have relatively brief durations of action. An ultralong-acting local anesthetic would benefit patients with acute and chronic pain. The authors prepared and characterized a novel liposomal bupivacaine formulation using remote loading of bupivacaine along an ammonium sulfate gradient and assessed its efficacy in humans. METHODS: A large multivesicular liposomal bupivacaine formulation was prepared by subjecting small unilamellar vesicles to successive freeze-and-thaw cycles. Bupivacaine hydrochloride was then remotely loaded into the liposomes along an ammonium sulfate gradient ([(NH4)2SO4)]intraliposome/[(NH4)2SO4)]medium > 1000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4 degree, 21 degree C, and 37 degree C; sterility; and pyrogenicity. Six subjects each received six intradermal injections in the lower back with 0.5 ml of 0.5, 1.0, and 2% liposomal bupivacaine; 0.5% standard bupivacaine; saline; and "empty" liposomes. Duration of analgesia was assessed using pinprick testing of the skin directly over the injection sites. Results were compared using the log-rank test. RESULTS: The mean large multivesicular vesicle size was 2439 +/- 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4 degree C. The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively. Neither saline nor "empty" liposomes produced analgesia. CONCLUSIONS: This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain.