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BACKGROUND: While conventional MRI sequences cannot visualize tissues from the osteochondral junction (OCJ) due to these tissues’ short transverse T(2)/T(2)* relaxations, ultrashort echo time (UTE) sequences can overcome this limitation. A 2D UTE sequence with a dual adiabatic inversion recovery preparation (DIR-UTE) for selective imaging of short T(2) tissues with high contrast has previously been developed, but high sensitivity to eddy currents and aliased out-of-slice excitation make it difficult to image the thin layer of the OCJ in vivo. Here, we combine the DIR scheme with a 3D UTE Cones sequence for volumetric imaging of OCJ tissues in vivo, aiming to generate higher OCJ contrast compared with a recently developed single IR-prepared UTE sequence with a fat saturation module (IR-FS-UTE). METHODS: All sequences were implemented on a 3T clinical scanner. The DIR-UTE Cones sequence combined a 3D UTE Cones sequence with two narrow-band adiabatic IR preparation pulses centered on water and fat spectrum frequencies, respectively. The 3D DIR-UTE Cones sequence was first applied to a phantom, then to the knees of four healthy volunteers and four patients diagnosed with osteoarthritis and compared to the IR-FS-UTE sequence. RESULTS: In both phantom and volunteer studies, the proposed DIR-UTE Cones sequence showed much higher contrast for OCJ imaging than the IR-FS-UTE sequence did. The 3D DIR-UTE Cones sequence showed a significantly higher contrast-to-noise ratio (CNR) between the OCJ and subchondral bone fat (BF) (mean, standard deviation (SD): 25.7 ± 2.3) and between the OCJ and superficial layers of cartilage (SC) (mean, SD: 22.2 ± 3.5) compared to the IR-FS-UTE sequence (mean, SD: 10.8 ± 2.5 and 16.3 ± 2.6, respectively). CONCLUSIONS: The 3D DIR-UTE Cones sequence is feasible for imaging of the OCJ region of the knee in vivo and produces both high resolution and high contrast.

Background and aimsWhile the United States has been experiencing an opioid epidemic, 29 states and Washington DC have legalized cannabis for medical use. This study examined whether state-wide medical cannabis legalization was associated with reduction in opioids received by Medicaid enrollees.DesignSecondary data analysis of state-level opioid prescription records from 1993-2014 Medicaid State Drug Utilization Data. Linear time-series regressions assessed the associations between medical cannabis legalization and opioid prescriptions, controlling for state-level time-varying policy covariates (such as prescription drug monitoring programs) and socio-economic covariates (such as income).SettingUnited States.ParticipantsDrug prescription records for patients enrolled in fee-for-service Medicaid programs that primarily provide health-care coverage to low-income and disabled people.MeasurementsThe primary outcomes were population-adjusted number, dosage and Medicaid spending on opioid prescriptions. Outcomes for Schedule II opioids (e.g. hydrocodone, oxycodone) and Schedule III opioids (e.g. codeine) were analyzed separately. The primary policy variable of interest was the implementation of state-wide medical cannabis legalization.FindingsFor Schedule III opioid prescriptions, medical cannabis legalization was associated with a 29.6% (P=0.03) reduction in number of prescriptions, 29.9% (P=0.02) reduction in dosage and 28.8% (P=0.04) reduction in related Medicaid spending. No evidence was found to support the associations between medical cannabis legalization and Schedule II opioid prescriptions. Permitting medical cannabis dispensaries was not associated with Schedule II or Schedule III opioid prescriptions after controlling for medical cannabis legalization. It was estimated that, if all the states had legalized medical cannabis by 2014, Medicaid annual spending on opioid prescriptions would be reduced by 17.8 million dollars.ConclusionState-wide medical cannabis legalization appears to have been associated with reductions in both prescriptions and dosages of Schedule III (but not Schedule II) opioids received by Medicaid enrollees in the United States.

Background The Patient Registry of Intrathecal Ziconotide Management (PRIZM) evaluated long-term effectiveness, safety, and tolerability of intrathecal ziconotide treatment in clinical practice. Methods Patient Registry of Intrathecal Ziconotide Management was an open-label, long-term, multicenter, observational study of adult patients with severe chronic pain. This interim analysis (data through July 10, 2015) of ziconotide as the first vs. not first intrathecal agent in pump included change from baseline in the Numeric Pain Rating Scale (NPRS; primary efficacy measure) and Patient Global Impression of Change (PGIC) scores. Results Enrollment closed at 93 patients; data collection was ongoing at the time of this interim analysis. Fifty-one patients (54.8%) received ziconotide as the first agent in pump (FIP+), whereas 42 (45.2%) did not (FIP−). Mean (SD) baseline NPRS scores were 7.4 (1.9) and 7.9 (1.6) in FIP+ and FIP− patients, respectively. Mean (SEM) percentage changes in NPRS scores were −29.4% (5.5%) in FIP+ patients (n = 26) and +6.4% (7.7%) in FIP− patients (n = 17) at month 6 and −34.4% (9.1%) in FIP+ patients (n = 14) and −3.4% (10.2%) in FIP− patients (n = 9) at month 12. Improvement from baseline, measured by PGIC score, was reported in 69.2% of FIP+ (n = 26) and 35.7% of FIP− (n = 14) patients at month 6 and 85.7% of FIP+ (n = 7) and 71.4% of FIP− (n = 7) patients at month 12. The most common adverse events (≥ 10% of patients overall as of the data cut) were nausea (19.6% vs. 7.1% of FIP+ vs. FIP− patients, respectively), confusional state (9.8% vs. 11.9%), and dizziness (13.7% vs. 7.1%). Conclusions Greater improvements in efficacy outcomes were observed when ziconotide was initiated as first-line intrathecal therapy vs. not first intrathecal agent in pump. The adverse event profile was consistent with the ziconotide prescribing information.

Experimental interventions that activate specific components of clinical pain are necessary for characterization of underlying mechanisms and pharmacology. Cutaneous hyperalgesia has been described that uses nonpainful heat to induce secondary hyperalgesia. This study evaluated the effect of intravenous alfentanil on experimental cutaneous hyperalgesia created using this method. Eighteen subjects participated in a randomized, double-blinded, placebo-controlled crossover study consisting of 2 sessions, 1 with alfentanil and 1 with placebo. Using a computer-controlled infusion pump, alfentanil or matching placebo was maintained at a constant plasma level of 75 ng/mL for 1 hour followed by the application of a 40°C heat stimulus to the right thenar eminence for 15 minutes. The temperature was raised by 1°C every 15 minutes until the subject reported pain or 45°C was reached. After the end point was reached, the temperature was maintained, and repeat testing was performed. The nonpainful heat created an area of secondary cutaneous hyperalgesia and significant decrease in mechanical pain threshold on heat-treated right vs untreated left during placebo administration. Alfentanil prevented the hypersensitivity when compared to placebo (P < .05) but failed to reduce the area of secondary hyperalgesia created by nonpainful heat when compared to placebo (P = .06). Neither alfentanil nor the heat lamp treatment showed any significant effect on other neurosensory measures. This study demonstrated a reliable production of cutaneous hyperalgesia using a nonpainful stimulus that is affected by the systemic delivery of alfentanil. This model for human cutaneous experimental pain may be a useful method for scientific characterization of analgesics.

We examined the UK’s effectiveness in reducing Child Mortality with 20 other Western countries, in thecontext of their national health expenditures, and, relative poverty — measured by ‘Income Inequality’the gap between top and bottom 20 per cent of income. W.H.O. Child (0–14) Mortality Rates (CMR) andGDP Expenditure on Health (% GDPHE) were examined and a cost-effectiveness ratio calculated, whichis the reduced CMR over the period divided by average GDPHE. The highest average % GDPHE wasUSA at 13.2 per cent; the UK’s 7.3 per cent was equal lowest. The widest Income Inequality was USA8.5 times; the UK at 7.2 was third widest. The highest CMR was the USA 2436 per million (pm), theUK’s 1630 pm, although representing a fall of 62 per cent was fourth highest. However, UK cost-effec-tiveness ratio (1: 350) was eighth best of 21 countries. Only Income Inequality correlated significantlywith CMR. UK CMR fell significantly more than five countries but ten others declined more. If UK deathshad been at the average of the 17 countries with lower CMR, there would have been 1827 fewer deaths.British children’s poverty and health expenditure means they and their services are doubly disadvantagedalthough the NHS relatively achieved more with comparatively less. © 2014 John Wiley & Sons Ltd andNational Children’s Bureau

Objective: This analysis was conducted to determine the likelihood of identifying an effective dose of fentanyl sublingual tablet during the initial titration phase of 2 clinical trials, to characterize the actual effective dose in patients achieving successful titration, and to examine the relationship between baseline characteristics and likelihood of achieving an effective dose. Methods: Data were derived from 2 clinical trials (Study 1, n = 131; Study 2, n = 139) of fentanyl sublingual tablet in patients with cancer-associated breakthrough pain (BTP). Both trials comprised a 2-week titration phase and 12-month maintenance phase. The initial dose was 100 μg, titrated to an effective dose (producing effective relief of all BTP episodes on 2 consecutive days) of 100 to 800 μg. Results: A total of 270 patients entered the titration phase. Mean (SD) baseline BTP opioid dose was 25.7 (88.9) mg morphine equivalent, and mean baseline around-the-clock opioid dose was 196.5 (151.6) mg morphine equivalent. Using conservative criteria for determining effective dose, 174 patients (64.4%) were successfully titrated to an effective dose (mean [SD], 498.2 [234.8] μg). The most frequent (27.6%) effective dose was 800 μg, and more than 85% of patients required an effective dose ≥ 300 μg. There were no significant relationships between any baseline characteristics and titration success. Conclusion: Despite stringent criteria, 64.4% of patients achieved an effective dose of fentanyl sublingual tablet within the dose range of 100 to 800 μg. Baseline characteristics were not identified to be associated with the likelihood of successful titration or with the actual effective dose of fentanyl sublingual tablet.

Herpes zoster infection is caused by a reactivation of the latent varicella zoster virus that causes chicken pox. It appears predominantly in older adults whose immunity for the virus has waned. The natural course of the disease is usually favorable, and the symptoms disappear spontaneously within a few weeks. Some patients, however, have prolonged pain: post-herpetic neuralgia. The diagnosis of acute zoster infection is made on the clinical signs including the appearance of rash. Post-herpetic neuralgia is described as sharp, burning, aching, or shooting constantly present in the dermatome that corresponds with the earlier rash. The objectives of treating herpes zoster are: (1) acute pain reduction; (2) promotion of recovery of epidermal defects and prevention of secondary infections; and (3) reduction or prevention of post-herpetic neuralgia. The objective of the treatment of post-herpetic neuralgia is primarily pain alleviation and improvement of the quality of life. Early treatment of the infection and the pain is believed to reduce the risk for post-herpetic neuralgia. This persistent pain syndrome is difficult to treat. Antiepileptic drugs and tricyclic antidepressants are the first choice. Interventional treatments, such as epidural injections of corticosteroids and local anesthetic drugs, have an effect on the acute pain but are of limited use in preventing post-herpetic neuralgia. When conservative treatment fails in providing satisfactory relief of post-herpetic neuralgia, a sympathetic block may be considered (2 C+); if this treatment provides unsatisfactory results, spinal cord stimulation may be considered, in a study context (2 C+).

Objective This tutorial on comparative statistics has been written in two complementary segments. The first paper (part A) focused on explaining the general concepts of the null hypothesis and statistical significance. This second article (part B) addresses the application of three specific statistical tests. These two articles should be read sequentially and the first article should be available for reference while one reads the second. Study design Tutorial. Methods The authors met weekly for 10 months to discuss clinical research articles and the applied statistics. The difficulty was not the material but the effort to make it easy to read and as short as possible. Results The article discusses the application of three common statistical indexes of contrast, chi2, Mann-Whitney U, and Student t-test and other concepts, such as sample size, degrees of freedom, errors, power, and confidence intervals. Conclusions Statistical tests generate a number known as a statistic (chi2, U, t), which is sometimes called a "critical ratio" because it helps us to make a decision. This number is then associated with a probability, or P value. Sample size is a crucial element in the initial design of a research project and in the subsequent ability of the results to show statistical significance if the difference is clinically important. The example data used in this paper demonstrate the application of the three specific tests and illustrate the effect of sample size on the results.

Neuropathic pain is a considerable burden that affects activities of daily living. The management of neuropathic pain can be challenging because of multiple etiologies and complex manifestations. Ziconotide is a nonopioid intrathecal (IT) analgesic option for patients with neuropathic pain refractory to conventional treatments. The objective of this article is to review the published literature on ziconotide for the treatment of neuropathic pain. Relevant publications were identified through searches of all years of 6 databases, which included PubMed, EMBASE, and CINAHL. Search terms used were ziconotide, SNX-111, MVIIA, Prialt, and neuropathic pain. Publications were included if ziconotide was intrathecally administered (either alone or in combination with other IT agents) to treat neuropathic pain of any etiology and if pain assessment was an outcome measure. Data extracted included study design, IT drug doses, pain outcome measures, and adverse events (AEs). Twenty-eight articles met the inclusion criteria: 5 were preclinical studies and 23 were clinical studies. In the preclinical studies, ziconotide demonstrated antiallodynic effects on neuropathic pain. Data from double-blind, placebo-controlled (DBPC) trials indicated that patients with neuropathic pain reported a mean percent improvement in pain score with ziconotide monotherapy that ranged from 15.7% to 31.6%. A low starting dose and slow titration of ziconotide resulted in an improved safety profile in the aforementioned trials. Common AEs associated with ziconotide include nausea and/or vomiting, dizziness, confusion, urinary retention, and somnolence. Evidence from DBPC trials, open-label studies, case series, and case studies suggests that ziconotide, as either monotherapy or in combination with other IT drugs, is a potential therapeutic option for patients with refractory neuropathic pain. Additional studies are needed to establish the long-term efficacy and safety of ziconotide for neuropathic pain.

Objectives/Hypothesis The present tutorial is the seventh in a series of Tutorials in Clinical Research. The specific purpose of the tutorial (Part A) and its sequel (Part B) is to introduce and explain three commonly used statistical tools for assessing contrast in the comparison between two groups. Study Design Tutorial. Methods The authors met weekly for 10 months discussing clinical research studies and the applied statistics. The difficulty was not in the material but in the effort to make the report easy to read and as short as possible. Results The tutorial is organized into two parts. Part A, which is the present report, focuses on the fundamental concepts of the null hypothesis and comparative statistical significance. The sequel, Part B, discusses the application of three common statistical indexes of contrast, the χ2, Mann-Whitney U, and Student t tests. Conclusions Assessing the validity of medical studies requires a working knowledge of research design and statistics; obtaining this knowledge need not be beyond the ability of the busy surgeon. The authors have tried to construct an accurate, easy-to-read, easy-to-apply, basic introduction to comparing two groups. The long-term goal of the present tutorial and others in the series is to facilitate basic understanding of clinical research, thereby stimulating reading of some of the numerous well-written research design and statistical texts. This knowledge may then be applied to the continuing educational review of the literature and the systematic prospective analysis of individual practices.

Objectives This is the sixth in a series of Tutorials in Clinical Research. The objectives of this tutorial are to produce a brief, step-by-step, user-friendly atlas with clinical scenarios and illustrative examples to serve as ready references and, it is hoped, to open an inviting door to understanding statistics. Study design Tutorial. Methods The authors met weekly for 6 months discussing clinical research articles and the applied statistics. Liberal use of reference texts and discussion focused on constructing a tutorial that is factual as well as easy to read and understand. Results The tutorial is organized into five sections: Overview, Key to Descriptive Summaries, Steps in Summarizing Descriptive Data, Understanding the Summaries of Specific Data Types, and Understanding Scope or Dispersion of Data. Conclusions Assessing the validity of medical studies requires a working knowledge of statistics; however, obtaining this knowledge need not be beyond the ability of the busy surgeon. Desire is the only limiting factor. We have tried to construct an accurate, basic, easy-to-read-and-apply introduction to the task of summarizing the characteristics of a single variable. This is known as descriptive statistics.

Objective This is the fourth of a series of Tutorials in Clinical Research. 1–3 The objectives of this article are to heighten reader awareness of biases and of methods to reduce their impact and to provide an easy reference document for the reader during future journal reading. Study Design Tutorial. Methods The authors met weekly for 4 months discussing clinical research articles and biases for which they might be at risk. Liberal use of reference texts and specific articles on bias were reviewed. Like the example by Sackett, biases were catalogued to create an easily understood reference. Articles were chosen to demonstrate how understanding bias might facilitate assessment of the validity of medical publications. Results The article is organized into three main sections. The first section introduces specific biases. Two tables serve as rapid reference tools. The second section describes the most common biases linked to specific research approaches and reviews techniques to minimize them. The last section demonstrates the application of the information to an article in a manner that can be applied to any article. Conclusions Assessing the validity of a medical publication requires an awareness of bias for which the research is inherently at risk. A review of the publication to determine what steps the authors did or did not undertake to minimize the impact of biases on their results and conclusions helps establish the validity. This article should be of assistance in this critical review task.

Recent technological advances claim to allow quantitative measurement of the functional integrity of both large and small diameter sensory nerve fibers using the current perception threshold (CPT) sensory testing device. This device has yet to be validated against the corresponding gold standard references for sensory testing (thermal sensory testing [TST]) and von Frey tactile hair stimulation [VF]) to correlate its evaluation of similar sensory nerve perceptions. A baseline neurosensory examination using the CPT, TST and VF methods was performed on 19 healthy volunteers. Using a randomized, double-blind, placebo-controlled design, each subject received an alfentanil or diphenhydramine (as a placebo control) infusion in separate study sessions. The order of the study sessions was randomized and separated by 1 week. The 3 neurosensory examinations were repeated at 3 different targeted plasma levels of study drug. Changes in neurosensory thresholds were then compared between the 3 methods. All CPT measurements and the cold pain measurement showed a significantly higher degree of variability than the other TST and VF measurements. There appeared to be a correlation between the CPT 5 Hz pain threshold and the TST cold pain and warm sensation; intravenous alfentanil significantly elevated all 3 detection thresholds. In addition, there was no effect of alfentanil on the VF or the CPT 2000 Hz thresholds. However, we did not see the predicted relation between the 250 Hz CPT stimulus and cool sensation. From these studies, there is some evidence that similar fiber tracts may be measured between the CPT, TST, and VF methods, especially with the CPT 5 Hz measures and C-fiber tract activity.

The purpose of this study is to evaluate both painless and painful sensory transmission in patients with Complex Regional Pain Syndrome (CRPS) using the automated electrodiagnostic sensory Nerve Conduction Threshold (sNCT) test. This test generates reliable, painless Current Perception Threshold (CPT) and atraumatic Pain Tolerance Threshold (PTT) measures. Standardized CPT and PTT measures using constant alternating current sinusoid waveform stimulus at 3 different frequencies 5 Hz, 250 Hz, and 2 kHz (Neurometer CPT/C Neurotron, Inc. Baltimore, MD) were obtained from CRPS subjects at a distal phalange of the affected extremity and at an ipsilateral asymptomatic control site. Matched sites were tested on healthy subjects. Detection sensitivities for an abnormal PTT and CPT test were calculated based on specificity of 90% as determined from data obtained from healthy controls. A Spearman rank correlation was used to test for a significant association between presence of allodynia and an abnormal PTT or CPT at any frequency tested. Thirty-six CRPS subjects and 57 healthy controls were tested. The highest detection sensitivity of the PTT test from symptomatic test sites was 63% for the finger and 71% for the toe. PTT abnormalities were also detected, to a lesser degree, at the asymptomatic control site (41% finger control site, 16% toe control site). The highest CPT detection sensitivity at the symptomatic site was 37% for the finger site and 53% for the toe site. CPT abnormalities were also detected at the asymptomatic control site (29% finger control site, 37% toe control site). Eighty-six percent of the CRPS subjects had either a PTT or CPT abnormality at any frequency at the symptomatic site. There was a significant correlation between presence of allodynia and presence of an abnormal CPT and PTT, respectively (P < .01). The correlation coefficient was lower for CPT than for PTT, ie, 0.34 versus 0.6 for the finger and 0.48 versus 0.67 for the toe, respectively. In studied CRPS patients an abnormal PTT was detected with higher sensitivity than an abnormal CPT. Assessing PTT may become a useful electrodiagnostic quantitative sensory test for diagnosing and following the course of neuropathic pain conditions.

Objective This is the first of a planned progressive series of articles entitled “Tutorials in Clinical Research” written to assist those who would become more active in the application of scientific methods to their practices and to assist those who would seek to develop and publish new discoveries of their own. On completion of Tutorials, the reader should be able to 1) critically and efficiently read the literature and 2) use his or her personal practice as a laboratory for clinical investigation. Study Design Tutorial. Methods The Journal editor agreed to launch the series “Tutorials in Clinical Research,” which was conceived out of a need for an easily understandable and accessible collection of tutorials for the busy practitioner. The Clinical Research Working Group at Washington University, Department of Otolaryngology—Head and Neck Surgery, will write, edit, and solicit additional authors for the completion of this planned 22-article series. The intended audience includes, among other groups, practitioners without research funds who are interested in the application of scientific methods to their practices. Results This first article in the series outlines how to begin and three steps for the initial application of scientific methods to practice, including critical literature review, prospective analysis of practice, and specific project development. Conclusions The application of scientific methods to practice can be fun, educational, and effective in the enhancement of quality care. The “value added” result is the development of the powerful 10-minute patient office visit for the busy practitioner.

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer-controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer-controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5μg/ml were targeted for 15 min at each concentration. A three-compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two-stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three-compartment mammillary model fit to the measured concentration using the pooled data approach were: V 1 = 7.44, V 2 =11.5 and V 3 = 97.71; Cl 1 = 0.585, Cl 2 = 2.23 and Cl 3 =1.64 Umin. Similarly calculated parameters using NONMEM were V 1 = 6.99, V 2 =12.2 and V 3 =1341; Cl 1 = 0.703, Cl 2 =1.24 and Cl 3 =1.49 Umin. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer-controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer-controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long-lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.

We have observed that spinal liposome administration in the rat resulted in in an allodynia evoked by light touch. We later determined that liposomes composed of D-isomer phospholipids were essentially non-toxic. This study examines the effects of alfentanil encapsulated in liposomes made from the natural L-isomer and synthetic D-isomer of dipalmitoyl phosphatidyl choline on antinoceiception, side effects, and algogenic behaviour. Both unilamellar and multilamellar liposomes were studied. Rats prepared with chronic intrathecal catheters received intrathecal injections of alfentanil (5 or 50 micrograms) in saline or encapsulated in liposomes composed of either L- or D-isomers of dipalmitoyl phosphatidyl choline (DPPC) in unilamellar or multilamellar liposome formulations. Antinociception was measured using the hot plate test (52.5 degrees). Side effects were measured by catalepsy, corneal responses, pinna response, righting reflex, and paw step. Allodynia was measured by lightly stroking the animal's back. Intrathecal alfentanil in saline or in the liposomes produced a dose-dependent increased latency in the hot plate response. Encapsulation of alfentanil in the liposomes produced a significant decrease in the loss of corneal, paw step and righting reflex and a slight decrease in catalepsy and loss of the pinna response. There was no significant difference between liposome preparations in preventing side effects. L-multilamellar-DPPC produced allodynia in 100% of the animals whereas significantly less allodynia was observed with the other preparations. This study indicates that liposomal preparations can significantly enhance the therapeutic ratio of a lipid soluble opioid after spinal delivery. However, the choice of lipids for the formulation of liposomes intended for spinal drug delivery must be considered since the L-isomer and larger lipid load of multilamellar liposomes have a direct spinal effect leading to alledynia. Previous studies have in fact shown that spinal lysolecithin can yield focal demyelination.