Intrathecal Space Research Articles

Optimal-mass-transfer-based estimation of glymphatic transport in living brain.

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the 'glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs1,2. It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through para-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach3 to derive the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data.

Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries

The environment within the spinal cord after injury, which changes in the progression from the acute to chronic stages, limits the extent of regeneration. The delivery of inductive factors to promote regeneration following spinal cord injury has been promising, yet, few strategies are versatile to allow delivery during acute or chronic injury that would facilitate screening of candidate therapies. This report investigates the intrathecal delivery of lentiviruses for long-term expression of regenerative factors. Lentivirus-filled sponges were inserted into the intrathecal space surrounding the spinal cord, with transgene expression observed within multiple cell types that persists for 12weeks for both intact and injured spinal cord, without any apparent damage to the spinal cord tissue. Sponges loaded with lentivirus encoding for Sonic hedgehog (Shh) were investigated for acute (delivered at 0weeks) and chronic (at 4weeks) injuries, and for multiple locations relative to the injury. In an acute model, sponges placed directly above the injury increased oligodendrocyte and decreased astrocyte presence. Sponges placed caudal to the injury had reduced impact on oligodendrocytes and astrocytes in the injury. In a chronic model, sponges increased oligodendrocyte and decreased astrocyte presence. Furthermore, the effect of Shh was shown to be mediated in part by reduction of Bmp signaling, monitored with an Msx2-sensitive reporter vector. The implantation of lentivirus-loaded biomaterials intrathecally provides the opportunity to induce the expression of a factor at a specified time without entering the spinal cord, and has the potential to promote gene delivery within the spinal cord, which can influence the extent of regeneration.

The Relationship Between the Mechanisms of Action and Safety Profiles of Intrathecal Morphine and Ziconotide: A Review of the Literature.

To better characterize safety profiles associated with the intrathecal (IT) administration of morphine and ziconotide and discuss how they relate to mechanisms of action. Published data were evaluated to identify potential relationships between safety profiles of IT morphine and IT ziconotide and their mechanisms of action. Potentially severe and clinically relevant adverse events (AEs) associated with IT morphine include respiratory depression, tolerance, and granuloma formulation, whereas IT ziconotide is associated with neuropsychiatric AEs, such as cognitive impairment, hallucinations, and changes in mood or consciousness, particularly with high doses and rapid titration. AEs associated with these IT therapies may result from spread of the medication out of the IT space into areas of the central and peripheral nervous systems and systemic circulation. AEs that occur usually can be managed and, in some cases, prevented. To mitigate risk, patients' histories should be reviewed to identify potential complicating factors (e.g., obesity or other risk factors for respiratory dysfunction in patients receiving IT morphine; a history of psychosis in patients receiving IT ziconotide). Also, treatment should be initiated at a low dose, titrated slowly, and patients should be closely monitored during treatment. IT morphine and IT ziconotide are approved by the US Food and Drug Administration for patients who do not respond to less invasive treatments, but the safety profiles of each may make them more or less appropriate for certain patient populations.

Does Spinal Block Through Tattooed Skin Cause Histological Changes in Nervous Tissue and Meninges?: An Experimental Model in Rabbits.

Although there is no documented evidence that tattoo pigments can cause neurological complications, the implications of performing neuraxial anesthesia through tattooed skin are unknown. In this study, we aimed to assess whether spinal puncture performed through tattooed skin of rabbits determines changes over the spinal cord and meninges. In addition, we sought to evaluate the presence of ink fragments entrapped in spinal needles. Thirty-six young male adult rabbits, each weighing between 3400 and 3900 g and having a spine length between 38.5 and 39 cm, were divided by lot into 3 groups as follows: GI, spinal puncture through tattooed skin; GII, spinal puncture through tattooed skin and saline injection; and GIII, spinal puncture through skin free of tattoo and saline injection. After intravenous anesthesia with ketamine and xylazine, the subarachnoid space was punctured at S1-S2 under ultrasound guidance with a 22-gauge 2½ Quincke needle. Animals in GII and GIII received 5 μL/cm of spinal length (0.2 mL) of saline intrathecally. In GI, the needle tip was placed into the yellow ligament, and no solution was injected into the intrathecal space; after tattooed skin puncture, 1 mL of saline was injected through the needle over a histological slide to prepare a smear that was dyed by the Giemsa method to enable tissue identification if present. All animals remained in captivity for 21 days under medical observation and were killed by decapitation. The lumbosacral spinal cord portion was removed for histological analysis using hematoxylin-eosin stain. None of the animals had impaired motor function or decreased nociception during the period of clinical observation. None of the animals from the control group (GIII) showed signs of injuries to meninges. In GII, however, 4 animals presented with signs of meningeal injury. The main histological changes observed were focal areas of perivascular lymphoplasmacyte infiltration in the pia mater and arachnoid. There was no signal of injury in neural tissue in any animal of both groups. Tissue coring containing ink pigments was noted in all GI smears from the spinal needles used to puncture the tattooed skin. On the basis of the present results, intrathecal injection of saline through a needle inserted through tattooed skin is capable of producing histological changes over the meninges of rabbits. Ink fragments were entrapped inside the spinal needles, despite the presence of a stylet.

No rent is small for migration of epidural catheter into sub-arachnoid space.

Sir, Epidural analgesia forms the mainstay of pain relief in abdominal surgeries.[1,2] Epidural needle placement and catheter insertion are preferably performed under local anaesthesia, before induction of general anaesthesia.[3] Dural puncture by the epidural needle is a known complication, and the reported incidence of accidental dural puncture varies from 0.4% to as high as 6%.[4] Dural puncture precludes the catheter placement in the same inter-vertebral space because rent created in the dura mater may allow intra-thecal migration of the epidural catheter. We report a case of inadvertent intra-thecal migration of the epidural catheter through a dural puncture by a 26 gauge needle. A 38-year-old male patient, height 167 cm and weight 63 kg. was posted for hepato-jejunostomy for the benign stricture of the common bile duct. After a written informed consent, patient was taken up for the surgery. As part of perioperative anaesthesia care, epidural catheter placement was planned in the sitting position. With all sterile precautions, inter-vertebral space between 8th and 9th thoracic vertebra was marked and was punctured with a 26 gauge 1½ inch long needle, for infiltration of local anaesthesia. An aspiration check before injecting the local anaesthetic revealed that probably dura mater had been punctured, and fluid, possibly cerebro-spinal fluid (CSF) was getting aspirated. A note of the depth at which dura mater was punctured was made. Because the dura mater was punctured with a 26 gauge needle, too small to be of concern, it was decided to use the same inter-vertebral space for epidural catheter placement. Epidural space was identified by the loss of resistance technique with a 16 Gauge 12 cm long Tuohy epidural needle (with catheter stabiliser). Skin to epidural space distance was 4 cm. There was no CSF leakage at the hub of the epidural needle. The epidural catheter was easily inserted through the needle but just as the catheter had crossed the mark of 14 cm at needle hub, fluid was seen flowing into the catheter. Fluid was aspirated into a syringe, and it was confirmed as CSF (temperature and sugar content of the aspirated fluid). Epidural catheter was then withdrawn and was placed in an inter-vertebral space higher up. Rest of the course of the hospital stay of the patient was uneventful. Dural puncture by epidural catheter on its own is not possible, though arachnoid puncture by the epidural catheter has been shown in an experimental study.[5] In our patient since dura mater and the arachnoid mater were punctured with a 26 G needle, it would have created a weak point through which subsequently the epidural catheter would have travelled into the intra-thecal space. Robbins et al. had also reported a similar case where accidental intra-thecal insertion of an extradural catheter happened during combined spinal-extradural anaesthesia.[6] They used a 26 gauge Whitacre spinal needle through 16 gauge Tuohy extradural needle. Physical characteristics like height and weight can be used to predict the depth of the epidural space to guide epidural needle placement. Ravi et al. in their study had concluded that the mean depth of epidural space in patients of body mass index (BMI) <30 is 41.60 ± 5.80 mm on the basis of a formula (Depth [mm] = a + b [BMI]. where a = 17.7966 and b = 0.9777).[7] Our patient with a calculated BMI of 22.6, the predicted depth of the epidural space was 39.89 mm. Whereas skin to sub-arachnoid space depth (SSD) in Indian males is reported to be 4.81 ± 0.68 cm,[8] the formula derived for determining SSD in the Indian population, 2.71 + 0.09 × BMI, predicts SSD of 4.74 cm for our patient.[8] We located the epidural space at 4 cm depth from the skin that was well within the predicted depth for epidural space, and was short of the predicted SSD. This also supports our observation that the epidural needle was indeed in the extradural space. In our case, that the epidural catheter migrated into the sub-arachnoid space in the absence of any undue force warrants caution. We suggest that caution should be exercised even while puncturing inter-vertebral space for infiltration for local anaesthesia and in case dural puncture happens, epidural puncture should not be attempted in the same inter-vertebral space.

Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep.

Amitriptyline (AMI) is a lipophilic, tricyclic antidepressant with analgesic properties that could potentially be used for epidural (EPI) analgesia. However, no pharmacokinetic data are available for AMI in spinal spaces. The objective of this study was to evaluate the spinal disposition and intrathecal (IT) bioavailability of AMI after IT and EPI administration. Six Lacaune ewes received 3 consecutive administrations of AMI. They initially received 10 mg of AMI administered intravenously, then 5 mg of AMI administered intrathecally, and 50 mg of AMI injected into the EPI space. Consecutive administrations were separated by intervals of 2 hours. A simultaneous microdialysis technique was used to determine the EPI and IT concentrations of AMI. Population analysis with S-ADAPT software was used to evaluate the pharmacokinetic parameters. Following intravenous administration, the clearance and central compartment (Vc) in plasma were 1.32 L/min and 147 L, respectively. Concentration-time profiles for the IT and EPI compartments were highly variable after transmeningeal diffusion. The IT Vc after IT administration and the EPI Vc after EPI administration were 2.4 and 48.9 mL, respectively. Less AMI transferred from the EPI to the IT space than from the IT to the EPI compartment, with bioavailabilities of 1.3% and 55%, respectively. Simultaneous population analysis for AMI demonstrated differences in EPI and IT pharmacokinetics following the EPI and IT administration of this drug. The IT bioavailability of AMI after EPI administration is relatively low.

Low-dose intrathecal local anesthetic does not increase the threshold current for the epidural stimulation test: a prospective observational trial of neuraxial analgesia in labouring women

The purpose of this study was to investigate the ability of the electrical epidural stimulation test (EST) to determine the position of the epidural catheter during combined spinal-epidural (CSE) anesthesia for labour analgesia. This was a prospective observational trial of attempted EST during neuraxial analgesia in labouring women. Ten women received a double-segment CSE technique and one woman underwent continuous spinal analgesia following inadvertent dural puncture and deliberate placement of the catheter tip in the intrathecal space. In all CSE cases, the spinal injection was performed below the level of the epidural insertion. The motor threshold current (MTC) was determined by EST through the existing epidural/intrathecal catheter immediately following and at five, ten, and 15 mins after intrathecal injection of bupivacaine 1.75mg and fentanyl 15μg. Changes in the MTC were expressed as a percent change compared with baseline. The MTC required to elicit muscle contractions in women with epidurally placed catheters was unaffected by the intrathecal injection of the analgesic mixture (P=0.731). The MTC increased following an intrathecal injection of the same mixture in a woman who had the catheter placed intrathecally. The intrathecal injection of a low dose of bupivacaine-fentanyl does not affect the MTC if the catheter is placed in the epidural space; however, it does affect the threshold if the catheter is placed intrathecally. We also confirm that the EST can help to determine the position of the epidural catheter prior to injection of the test dose. This trial was registered at ClinicalTrials.gov (NCT00464841).

Http://www.medultrason.ro/ultrasound-in-the-examination-of-the-gallbladder-a-holistic-approach-grey-scale-doppler-ceus-elastography-and-3d/

Neuraxial blockade is still largely performed as a blind procedure. Despite of developments in the type of needles used and drugs administered, the process of locating the epidural or intra-thecal space is still limited to identification of landmarks by palpation and reliance on tactile feedback of the operator. Ultrasound has provided the long needed "eye" to the procedure and has already shown promise of improving the safety and efficacy or neuraxial blocks. This review focuses on understanding the sonoanatomy of the neuraxial space, performing a systematic pre-procedural ultrasound scan, and reviewing the available evidence.

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs.

Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 10(12) genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the CSF and serum of dogs. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals, suggesting a strong case for further development toward clinical testing.

Human NgR-Fc decoy protein via lumbar intrathecal bolus administration enhances recovery from rat spinal cord contusion.

Axonal growth and neurological recovery after traumatic spinal cord injury (SCI) is limited by the presence of inhibitory proteins in myelin, several of which act via the NgR1 protein in neurons. A truncated soluble ligand-binding fragment of NgR1 serves as a decoy and promotes recovery in acute and chronic rodent SCI models. To develop the translational potential of these observations, we created a human sequence-derived NgR1(310)-Fc protein. This protein is active in vitro. When the human NgR1 decoy is administered by continuous intracerebroventricular infusion to rats with a spinal contusion injury at doses of 0.09-0.53 mg/kg/d, neurological recovery is improved. Effective doses double the percentage of rats able to bear weight on their hindlimbs. Next, we considered the half-life and distribution of NgR1(310)-Fc after bolus delivery to the lumbar intrathecal space. The protein is found throughout the neuraxis and has a tissue half-life of approximately 2 days in the rat, and 5 days in the nonhuman primate. At an intermittent, once every 4 day, lumbar bolus dosing schedule of 0.14 mg/kg/d, NgR1(310)-Fc promoted locomotor rat recovery from spinal cord contusion at least as effectively as continuous infusion in open field and grid walking tasks. Moreover, the intermittent lumbar NgR1(310)-Fc treatment increased the growth of raphespinal axons into the lumbar spinal cord after injury. Thus, human NgR1(310)-Fc provides effective treatment for recovery from traumatic SCI in this preclinical model with a simplified administration regimen that facilitates clinical testing.

Spinal anesthesia revisited: toxicity of new and old drugs and compounds.

Neural toxicity of substances injected into the intrathecal space has been a matter of debate since the introduction of spinal anesthesia in clinical practice. In recent years, new local anesthetics and adjuvants have been proposed for intrathecal use, and new techniques such as the use of ultrasound have been propagated. The present review summarizes recent clinical and experimental data on the neurotoxic effects of drugs and substances used for or in conjunction with spinal anesthesia. Chloroprocaine has been demonstrated to be associated with a lower risk of transient neurologic symptoms compared with lidocaine. However, despite extensive research, the issue of chloroprocaine or bisulfite neurotoxicity has not yet been resolved.Recent experimental data have identified a smaller neurotoxic potential for ropivacaine compared to levobupivacaine, procaine and bupivacaine. The addition of epinephrine has not been shown to increase lidocaine neurotoxicity. In-vivo experimental data suggest that lidocaine and bupivacaine neurotoxicity is not enhanced in diabetic patients.Furthermore, intrathecal introduction of aqueous ultrasound gel has been demonstrated to cause a distinct neuroinflammatory reaction. Finally, a large cohort study did not find the use of chlorhexidine gluconate for skin disinfection before neuraxial block to be associated with the risk of adhesive arachnoiditis. Clinical data suggest a high safety profile for intrathecal drugs and substances used for or in conjunction with spinal anesthesia. Recent experimental models for toxicity have provided further insight into the mechanisms and demonstrated possible, albeit clinically small differences in the relative neurotoxic potential of intrathecal drugs. This may contribute to a further increase in the safe use of spinal anesthesia in the clinical setting.

Programmable intrathecal pumps for the management of chronic pain: recommendations for improved efficiency.

The management of chronic pain can be very challenging. Often, physicians employ intrathecal (IT) drug delivery systems as a last resort to relieve intractable pain. The system consists of an implantable pump that stores and delivers medication through a catheter to the IT space. Programmability is achieved by positioning an external devise over the implanted pump to change the mode of drug delivery. The innovations in programmable IT drug delivery systems are expanding more rapidly than ever before. Unfortunately, the rapid expansion is accompanied by a lack of prospective randomized trials examining these new options. In an effort to improve results and reduce side effects, publications by experts or expert consensus panels provide guidance for the community. The purpose of this article is to provide a summary of high interest topics in recent publications.

Influence of intrathecal delivery of bone marrow-derived mesenchymal stem cells on spinal inflammation and pain hypersensitivity in a rat model of peripheral nerve injury.

BackgroundMultipotent mesenchymal stem (stromal) cells (MSCs) have been credited with immunomodulative properties, supporting beneficial outcomes when transplanted into a variety of disease models involving inflammation. Potential mechanisms include the secretion of paracrine factors and the establishment of a neurotrophic microenvironment. To test the hypothesis that MSCs release soluble mediators that can attenuate local inflammation, we here analysed the influence of MSCs on the activation of microglia cells, as well as on inflammatory parameters and pain behaviour in a surgical rat model of neuropathic pain.MethodsWe focussed on an experimental model of partial sciatic nerve ligation (PSNL), characterised by a rapid and persistent inflammation in the dorsal lumbar spinal cord where sensory inputs from the sciatic nerve are processed. Via indwelling intrathecal catheters, MSCs were repetitively grafted into the intrathecal lumbar space. Animals were evaluated for mechanical and thermal hypersensitivity over a period of 21 days after PSNL. Afterwards, spinal cords were processed for immunohistochemical analysis of the microglial marker ionized calcium-binding adapter molecule 1 (Iba1) and quantification of inflammatory markers in ipsilateral dorsal horns. We hypothesised that injections on postsurgical days 2 to 4 would interfere with microglial activation, leading to a reduced production of pro-inflammatory cytokines and amelioration of pain behaviour.ResultsPSNL-induced mechanical allodynia or heat hyperalgesia were not influenced by MSC transplantation, and spinal cord inflammatory processes remained largely unaffected. Indeed, the early microglial response to PSNL characterised by increased Iba1 expression in the lumbar dorsal horn was not significantly altered and cytokine levels in the spinal cord at 21 days after surgery were similar to those found in vehicle-injected animals. Grafted MSCs were detected close to the pia mater, but were absent within the spinal cord parenchyma.ConclusionsWe conclude that intrathecal administration is not an appropriate route to deliver cells for treatment of acute spinal cord inflammation as it leads to entrapment of grafted cells within the pia mater. We propose that the early inflammatory response triggered by PSNL in the lumbar spinal cord failed to effectively recruit MSCs or was insufficient to disturb the tissue integrity so as to allow MSCs to penetrate the spinal cord parenchyma.

The use of electrical stimulation to guide epidural and intrathecal needle advancement at the L5-L6 intervertebral space in dogs

ObjectiveTo determine the minimal electrical threshold (MET) necessary to elicit appropriate muscle contraction when the tip of an insulated needle is positioned epidurally or intrathecally at the L5-6 intervertebral space (phase-I) and to determine whether the application of a fixed electrical current during its advancement could indicate needle entry into the intrathecal space (phase-II) in dogs. Study designProspective, blinded study. AnimalsThirteen (phase-I) and seventeen (phase-II) dogs, scheduled for a surgical procedure where L5-6 intrathecal administration was indicated. MethodsUnder general anesthesia, an insulated needle was first inserted into the L5-6 epidural space and secondly into the intrathecal space and the MET necessary to obtain a muscular contraction of the pelvic limb or tail at each site was determined (phase-I). Under similar conditions, in dogs of phase-II an insulated needle was inserted through the L5-6 intervertebral space guided by the use of a fixed electrical current (0.8 mA) until muscular contraction of the pelvic limb or tail was obtained. Intrathecal needle placement was confirmed by either free flow of cerebrospinal fluid (CSF) or myelography. ResultsThe current required to elicit a motor response was significantly lower (p < 0.0001) when the tip of the needle was in the intrathecal space (0.48 ± 0.10 mA) than when it was located epidurally (2.56 ± 0.57). The use of a fixed electrical stimulation current of 0.8 mA resulted in correct prediction of intrathecal injection, corroborated by either free flow of CSF (n = 12) or iohexol distribution pattern (n = 5), in 100% of the cases. Conclusion and clinical relevanceNerve stimulation may be employed as a tool to distinguish epidural from intrathecal insulated needle position at the L5-6 intervertebral space in dogs. This study demonstrates the feasibility of using an electrical stimulation test to confirm intrathecal needle position in dogs.

Intrathecal Drug Delivery (ITDD) systems for cancer pain.

Intrathecal drug delivery is an effective pain management option for patients with chronic and cancer pain. The delivery of drugs into the intrathecal space provides superior analgesia with smaller doses of analgesics to minimize side effects while significantly improving quality of life. This article aims to provide a general overview of the use of intrathecal drug delivery to manage pain, dosing recommendations, potential risks and complications, and growing trends in the field.

Antibody-based techniques for detection of Lyme disease: a challenging issue

Antibody-based techniques for detection of Lyme disease: a challenging issue Joanna M Zajkowska Department of Infectious Diseases and Neuroinfections, Medical University in Bialystok, Bialystok, Poland Abstract: Serologic assays detecting antibodies to Borrelia burgdorferi are useful in the routine diagnosis of Lyme disease. Despite the presence of new and improved assays, current laboratory diagnosis still requires optimization. The variety of genospecies and their different geographic distributions are the reasons why standards and recommendations are not the same for all of the main geographic regions, ie, USA, Asia, and Europe. Moreover, the variety and variability of antigens represents a significant challenge in assay design. This is due to the various antigens among the genospecies responsible for Lyme borreliosis; the changing antigens presented during infection; and the variability of single antigens. This review article discusses the immunologic response in Lyme disease over time, and the advantages and disadvantages of existing serological tests. Two tier testing is also introduced. Antigens useful for diagnosis, the properties of individual antigens and their appearance in infection - especially the antigens appearing during mammalian infection, so-called &ldquo;in vivo&rdquo; antigens are introduced. To determine antibodies confirming infection in the nervous system, the same restrictions with regard to interpretation of enzyme-linked immunosorbent assay results in serum apply to cerebrospinal fluid. Furthermore, concentrations of antibodies in the two compartments, ie, blood and cerebrospinal fluid, are variable depending on compartmentalization (anatomic sequestration) and immunologic phenomena at immunologically privileged sites, such as the intrathecal space. To confirm neuroborreliosis, synthesis of antibodies in cerebrospinal fluid, should be measured in the form of a so-called antibody index. Further studies should focus on detecting the lowest concentration of antibodies and looking for useful new antigens, and the relationship between composition of such antigens and the patient&#39;s clinical status. Keywords: Lyme borreliosis, antigens, serologic techniques, antibodies detection, immunological response, antibody index, neuroborreliosis

Clinical Relevance of Pharmacological and Physiological Data in Intrathecal Baclofen Therapy

ObjectiveTo review all pharmacological and physiological data available on intrathecal baclofen (ITB) therapy and to evaluate its use in clinical practice and future research. Data SourcesPubMed was searched for relevant anatomic, physiological, and pharmacological data available on ITB. Study SelectionAll currently available data on ITB pharmacokinetics (PKs) and pharmacodynamics (PDs) in both human and animal studies were reviewed and combined with the anatomy and physiology of the intrathecal space and cerebrospinal fluid flow. Data ExtractionOnly 4 studies reported PK data on ITB in humans. More studies reported PD data on ITB; however, none were combined with PK data. More detailed data on PK could be gathered from studies using an animal model. Data SynthesisITB does not spread equally over the intrathecal space after injection, but it diffuses according to a concentration gradient. ITB distribution can be influenced by the location of the catheter tip and by changing the infusion mode. ConclusionsThe pharmacological and physiological data on ITB can be used to support decisions in clinical practice concerning drug concentration, infusion regimens, localization of the catheter tip, and management of tolerance; however, some strategies have little evidence in humans.

The effects of glucocorticoids on neuropathic pain: a review with emphasis on intrathecal methylprednisolone acetate delivery.

Methylprednisolone acetate (MPA) has a long history of use in the treatment of sciatic pain and other neuropathic pain syndromes. In several of these syndromes, MPA is administered in the epidural space. On a limited basis, MPA has also been injected intrathecally in patients suffering from postherpetic neuralgia and complex regional pain syndrome. The reports on efficacy of intrathecal administration of MPA in neuropathic pain patients are contradictory, and safety is debated. In this review, we broadly consider mechanisms whereby glucocorticoids exert their action on spinal cascades relevant to the pain arising after nerve injury and inflammation. We then focus on the characteristics of the actions of MPA in pharmacokinetics, efficacy, and safety when administered in the intrathecal space.

Potentiation of [Met5]enkephalin-induced antinociception by mixture of three peptidase inhibitors in rat

Previous in vitro studies have shown that degradation of opioid peptides during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), namely, amastatin, captopril, and phosphoramidon. In the present in vivo study, we evaluate the effects of intrathecal administration of these PIs on antinociception by [Met(5)]enkephalin (ME) or PIs themselves. Drugs were administered into the thoracolumbar level of the spinal cord in the intrathecal space in rat. Induction of antinociception was measured by the tail immersion assay, with 55°C as the nociceptive stimulus. Effects of PIs on antinociception were evaluated by dose-response study (ME, 1-20nmol; PIs, 1-20nmol each), by comparison of differences among two combinations of PIs (amastatin and captopril; captopril and phosphoramidon; amastatin and phosphoramidon) and three PIs (amastatin, captopril, and phosphoramidon), and by using opioid receptor selective antagonists. Intrathecal administration of ME with these three PIs or PIs alone significantly and dose dependently increased antinociception in a μ- and δ-opioid receptor antagonist-reversible manner; moreover, the degree of antinociception with a combination of any two of these was less than that with all three, indicating that any residual single peptidase could inactivate significant amounts of ME. The present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in inactivation of opioid peptides at the spinal level.

Intrathecal drug delivery systems

Anaesthetists have made use of the intrathecal (IT) space to provide optimum anaesthesia and analgesia for decades. Most commonly to tide the patient through the operative period, but also for postoperative pain relief. The advantages of the techniques and the comparative effectiveness of the drugs compared with other methods of administration are well known. Those of us who work in the field of chronic pain management are faced with providing relative analgesia over days and weeks for terminal cancer patients, months and years for those with progressive cancer-related pain and over decades for those with intractable pain of either malignant or non-malignant aetiology. We can do this to a great extent with the intrathecal drug delivery (ITDD) systems currently available. There are, of course, many treatment options available for patients with chronic pain and ITDD systems are by no means a first-line treatment, but in selected patients both can relieve pain and restore the quality of life in the short and long terms. It should be possible to relieve pain below the diaphragm with relative ease. Above the diaphragm, the effects of drugs on the cardio-vascular system may limit the use of effective doses of drugs. ITDD is an evolving therapy, and current drugs and practice may change in the light of new information.