Multiple Routes Of Administration Research Articles

Opportunities and Challenges for Niosomes as Drug Delivery Systems.

With the increase in drug resistance observed in most infectious diseases as well as some forms of cancer, and with the chances of development of new drug molecules to address this issue looking bleak, one of the most plausible ways to disease treatment is combination therapy. Combination therapy would ensure delay in drug resistance, if utilized rationally. However, the biggest difficulty in employing combination therapy are adverse effects due to potential drug-drug interactions and patient compliance due to multiple routes of administration or multiple dosing that may be required. To overcome these issues, researchers have utilized nanoparticle-based systems that can hold multiple drugs in a single carrier. There are several nanocarrier systems available for such purposes. However, the focus of this review will be non-ionic surfactant-based systems (niosomes) for delivery of multiple therapeutic agents. Niosomes are artificially prepared drug delivery carriers. They are structurally similar to liposomes albeit more stable than them. Literature pertaining to combination drug delivery and various drug delivery systems was reviewed. It was conceptualized that many of the methods used to prepare various types of carriers for combination delivery of drugs may be used for niosomal systems as well. We envisage that niosomes may effectively be utilized to package older drugs in newer ways. The review will thus focus on techniques that may be used for the formulation of niosomes, ways to encapsulate multiple-drug moieties, and challenges associated in preparing and optimizing such systems.

Intra uterine extra-amniotic versus vaginal misoprostol for termination of second trimester miscarriage: A randomized controlled trial

Termination of pregnancy in the second trimester using prostaglandins has been shown to be safe and effective. Misoprostol has multiple routes of administration; oral, vaginal, buccal, rectal and sublingual. The study aims to compare the efficacy and safety of intrauterine extra-amniotic and vaginal misoprostol in a dose of 200 microgram every 4 hours for the termination of pregnancy in cases of second trimester miscarriage. A prospective randomized open labeled clinical trial included 180 women with missed miscarriage in gestational age between 13 and 24 wks. Patients were randomized to receive subsequent doses of 200 µg misoprostol every 4 hrs either intra uterine extra-amniotic by Foley catheter or vaginally administered. Randomization was completed using a computer-generated random table. The primary outcome of this study was the mean duration from the initial misoprostol dose until complete fetal expulsion (induction-expulsion interval). The mean gestational age was 17.74 wks. The mean time to complete miscarriage in the intra uterine extra-amniotic group was 5.27 hrs, which was significantly lower than the vaginal group (9.92 hrs, p=0.001). Side effects were more common in vaginal group. Intra uterine extra-amniotic misoprostol with a dose of 200 µg every 4 hrs appears to be more effective and safer than vaginal misoprostol in induction of second trimester miscarriage.

Hyaluronic Acid Molecular Weight Determines Lung Clearance and Biodistribution after Instillation

Hyaluronic acid (HA) has emerged as a versatile polymer for drug delivery. Multiple commercial products utilize HA, it can be obtained in a variety of molecular weights, and it offers chemical handles for cross-linkers, drugs, or imaging agents. Previous studies have investigated multiple administration routes, but the absorption, biodistribution, and pharmacokinetics of HA after delivery to the lung is relatively unknown. Here, pharmacokinetic parameters were investigated by delivering different molecular weights of HA (between 7 and 741 kDa) to the lungs of mice. HA was labeled with either a near-infrared dye or with iodine-125 conjugated to HA using a tyrosine linker. In initial studies, dye-labeled HA was instilled into the lungs and fluorescent images of organs were collected at 1, 8, and 24 h post administration. Data suggested longer lung persistence of higher molecular weight HA, but signal diminished for all molecular weights at 8 h. To better quantitate pharmacokinetic parameters, different molecular weights of iodine-125 labeled HA were instilled and organ radioactivity was determined after 1, 2, 4, 6, and 8 h. The data showed that, after instillation, the lungs contained the highest levels of HA, as expected, followed by the gastrointestinal tract. Smaller molecular weights of HA showed more rapid systemic distribution, while 67 and 215 kDa HA showed longer persistence in the lungs. Lung exposure appeared to be optimum in this size range due to the rapid absorption of <67 kDa HA and the poor lung penetration and mucociliary clearance of viscous solutions of HA > 215 kDa. The versatility of HA molecular weight and conjugation chemistries may, therefore, provide new opportunities to extend pulmonary drug exposure and potentially facilitate access to lymph nodes draining the pulmonary bed.

Patterns of Drug Use, Risky Behavior, and Health Status Among Persons Who Inject Drugs Living in San Diego, California: A Latent Class Analysis

Background: Among persons who inject drugs (PWID), polydrug use (the practice of mixing multiple drugs/alcohol sequentially or simultaneously) increases risk for HIV transmission and unintentional overdose deaths. Research has shown local drug markets influence drug use practices. However, little is known about the impact of drug mixing in markets dominated by black tar heroin and methamphetamine, such as the western United States. Methods: Data were collected through an ongoing longitudinal study examining drug use, risk behavior, and health status among PWID. Latent class analysis (LCA) was used to identify patterns of substance use (heroin, methamphetamine, prescription drugs, alcohol, and marijuana) via multiple administration routes (injecting, smoking, and swallowing). Logistic regression was used to identify behaviors and health indicators associated with drug use class. Results: The sample included 511 mostly white (51.5%) males (73.8%), with mean age of 43.5 years. Two distinct classes of drug users predominated: methamphetamine by multiple routes (51%) and heroin by injection (49%). In multivariable logistic regression, class membership was associated with age, race, and housing status. PWID who were HIV-seropositive and reported prior sexually transmitted infections had increased odds of belonging to the methamphetamine class. Those who were HCV positive and reported previous opioid overdose had an increased odds of being in the primarily heroin injection class (all P-values < .05). Conclusion: Risk behaviors and health outcomes differed between PWID who primarily inject heroin vs. those who use methamphetamine. The findings suggest that in a region where PWID mainly use black tar heroin or methamphetamine, interventions tailored to sub-populations of PWID could improve effectiveness.

SiRNA-based therapies for pulmonary diseases.

Various delivery strategies, involving siRNA as a therapeutic tool for gene silencing, have been highlighted through several investigations all over the world. One such medical target, where the siRNA-based therapies have been immensely explored and have met with considerable success, is the area of pulmonary disorders. Lung diseases have presented themselves as attractive targets for studying siRNA-mediated cures due to their widespread persistence and lethality. Another interesting feature in this case is that the lung is accessible to therapeutic agents via multiple administration routes including the nasal, oral and intravenous routes. Recent advances in pulmonary delivery highlight the exploitation of all these routes for administration of siRNA-based therapies, particularly by employing non-viral carriers like nanoparticles. Through this manuscript we aim to provide a comprehensive overview of the most important and the latest developments in non-viral siRNA delivery for lung diseases. We have focused our discussion on the diverse systems, which have been investigated for a plethora of pulmonary disorders, ranging from inflammatory conditions like asthma and COPD, to infectious diseases like tuberculosis, and to lung cancer. An overview of the preclinical and clinical investigations conducted in this area has also been presented to the readers. While a variety of these systems have been found to be promising in pre-clinical studies, their successful transition as therapeutics will ultimately depend upon their clinical safety and efficacy, as well as the specificity of the carriers and methods employed for their administration.

Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders.

Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer’s disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer’s pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer’s mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer’s, Parkinson’s, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer’s disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

Inhibition of Carbonic Anhydrase Augments GABAA Receptor-Mediated Analgesia via a Spinal Mechanism of Action

Peripheral nerve injury (PNI) negatively influences spinal gamma-aminobutyric acid (GABA)ergic networks via a reduction in the neuron-specific potassium-chloride (K+-Cl–) cotransporter (KCC2). This process has been linked to the emergence of neuropathic allodynia. In vivo pharmacologic and modeling studies show that a loss of KCC2 function results in a decrease in the efficacy of GABAA-mediated spinal inhibition. One potential strategy to mitigate this effect entails inhibition of carbonic anhydrase activity to reduce HCO3–-dependent depolarization via GABAA receptors when KCC2 function is compromised. We have tested this hypothesis here. Our results show that, similarly to when KCC2 is pharmacologically blocked, PNI causes a loss of analgesic effect for neurosteroid GABAA allosteric modulators at maximally effective doses in naïve mice in the tail-flick test. Remarkably, inhibition of carbonic anhydrase activity with intrathecal acetazolamide rapidly restores an analgesic effect for these compounds, suggesting an important role of carbonic anhydrase activity in regulating GABAA-mediated analgesia after PNI. Moreover, spinal acetazolamide administration leads to a profound reduction in the mouse formalin pain test, indicating that spinal carbonic anhydrase inhibition produces analgesia when primary afferent activity is driven by chemical mediators. Finally, we demonstrate that systemic administration of acetazolamide to rats with PNI produces an antiallodynic effect by itself and an enhancement of the peak analgesic effect with a change in the shape of the dose-response curve of the α1-sparing benzodiazepine L-838,417. Thus, carbonic anhydrase inhibition mitigates the negative effects of loss of KCC2 function after nerve injury in multiple species and through multiple administration routes resulting in an enhancement of analgesic effects for several GABAA allosteric modulators. We suggest that carbonic anhydrase inhibitors, many of which are clinically available, might be advantageously employed for the treatment of pathologic pain states. PerspectiveUsing behavioral pharmacology techniques, we show that spinal GABAA-mediated analgesia can be augmented, especially following nerve injury, via inhibition of carbonic anhydrases. Carbonic anhydrase inhibition alone also produces analgesia, suggesting these enzymes might be targeted for the treatment of pain.

Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice

Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice

Methotrimeprazine for the management of End-Of-Life Symptoms in Infants and Children

This retrospective chart review assessed the efficacy, dose, and safety of methotrimeprazine in palliating end-of-life symptoms in children and infants. A retrospective chart review was conducted of 18 hospitalized pediatric patients who were treated with methotrimeprazine in their last two weeks of life. Data collected included age, diagnosis, symptoms, methotrimeprazine dose, route, efficacy, and any documented adverse effects. Patients' ages ranged from 16 days to 17 years. Underlying conditions included malignancies, trauma, and various neurodegenerative and congenital diseases. All patients (n = 18) were treated for symptoms of agitation, delirium, or restlessness. Most patients also experienced respiratory secretions/congestion (n = 15), pain (n = 13), and/ or dyspnea (n = 9). Less common symptoms included nausea/emesis (n = 5) and spasticity (n = 1). Methotrimeprazine dosages ranged from 0.02 mg/kg/dose to 0.5 mg/kg/dose. Routes of administration included intravenous (n = 13), oral/gastrostomy tube (n = 6), or subcutaneous (n = 4). Sedation (n = 6) was the only documented adverse effect, although when agitation was present, this was potentially an intended and perceived-to-be-beneficial effect. Methotrimeprazine, an old drug with diverse receptor activity and multiple routes of administration, appears to be an effective tool in treating complicated end-of-life symptoms in children and infants. This study provides a foundation for analysis with prospective and comparative trials, which may further quantify its benefit.

Nausea and Vomiting in Advanced Cancer- “The Cleveland Clinic Protocol”

Nausea and vomiting are common and distressing symptoms in advanced cancer. Both are multifactorial and cause significant morbidity, nutritional failure, and reduced quality of life. Assessment includes a detailed history, physical examination and investigations for reversible causes. Assessment and management will be influenced by performance status, prognosis, and goals of care. Several drug classes are effective with some having the added benefit of multiple routes of administration. It is our institution's practice to recommend metoclopramide as the first drug with haloperidol as an alternative antiemetic. Dexamethasone should be used for patients with central nervous system metastases or bowel obstruction. If your patient is near death, empiric metoclopramide, haloperidol or chlorpromazine is used without further investigation. For patients with a better prognosis, we exclude reversible causes and use the same first-line antiemetics, metoclopramide and haloperidol. For those who do not respond to first-line single antiemetics, olanzapine is second line and ondansetron is third. Rarely do we use combination therapy or cannabinoids. Olanzapine as a single agent has a distinct advantage over antiemetic combinations. It improves compliance, reduces drug interactions and has several routes of administration. Antiemetics, anticholinergics, octreotide and dexamethasone are used in combination to treat bowel obstruction. In opiod-na'ive patients, we prefer haloperidol, glycopyrrolate and an opioid as the first-line treatment and add or substitute octreotide and dexamethasone in those who do not respond. Non-pharmacologic interventions (mechanical stents and percutaneous endoscopic gastrostomy tubes) are used when nausea is refractory to medical management or for home-going management to relieve symptoms, reduce drug costs and rehospitalization.

Recombinant Parainfluenza Virus 5 Vaccine Encoding the Influenza Virus Hemagglutinin Protects against H5N1 Highly Pathogenic Avian Influenza Virus Infection following Intranasal or Intramuscular Vaccination of BALB/c Mice

New approaches for vaccination to prevent influenza virus infection are needed. Emerging viruses, such as the H5N1 highly pathogenic avian influenza (HPAI) virus, pose not only pandemic threats but also challenges in vaccine development and production. Parainfluenza virus 5 (PIV5) is an appealing vector for vaccine development, and we have previously shown that intranasal immunization with PIV5 expressing the hemagglutinin from influenza virus was protective against influenza virus challenge (S. M. Tompkins, Y. Lin, G. P. Leser, K. A. Kramer, D. L. Haas, E. W. Howerth, J. Xu, M. J. Kennett, J. E. Durbin, R. A. Tripp, R. A. Lamb, and B. He, Virology 362:139-150, 2007). While intranasal immunization is an appealing approach, PIV5 may have the potential to be utilized in other formats, prompting us to test the efficacy of rPIV5-H5, which encodes the HA from H5N1 HPAI virus, in different vaccination schemes. In the BALB/c mouse model, a single intramuscular or intranasal immunization with a live rPIV5-H5 (ZL46) rapidly induced robust neutralizing serum antibody responses and protected against HPAI challenge, although mucosal IgA responses primed by intranasal immunization more effectively controlled virus replication in the lung. The rPIV5-H5 vaccine incorporated the H5 HA into the virion, so we tested the efficacy of an inactivated form of the vaccine. Inactivated rPIV5-H5 primed neutralizing serum antibody responses and controlled H5N1 virus replication; however, similar to other H5 antigen vaccines, it required a booster immunization to prime protective immune responses. Taken together, these results suggest that rPIV5-HA vaccines and H5-specific vaccines in particular can be utilized in multiple formats and by multiple routes of administration. This could avoid potential contraindications based on intranasal administration alone and provide opportunities for broader applications with the use of a single vaccine vector.

Addiction à la cocaïne et aux psychostimulants

Due to many available forms (powder, pasta base, freebase and crack…) and because of multiple routes of administration (intranasal, intravenous, or smoked), cocaine has become in 30 years one of the most consumed illegal drugs worldwide, after cannabis. While the frequency of consumption decreases in North America, it continues to rise in Europe, and in some countries in South America, including Brazil, despite a growing knowledge of its specific effects, physical complications and psychiatric consequences. Elsewhere (notably in Asia and Indian Ocean), amphetamine and other stimulants (including methamphetamine), whose properties and patterns of use are very similar to those of cocaine, tend to replace it. Another amphetamine derivative, MDMA or ecstasy, is also consumed by many young people of less than 25 years, in Europe and North America, in a festive setting, with specific consequences and special procedures of care. Although there is currently no consensus for a specific medication, the most appropriate therapeutic approach seems to involve a psychosocial treatment associated with an anticraving medication, which will reduce compulsive desire to consume, in order to facilitate the psychotherapeutic and social care. However, pharmacological research remains very active, and many options are explored (GABAergic or dopaminergic agonists, amphetamine derivatives with long half-life, vaccine…), whether to treat addiction to cocaine or to methamphetamine.

Heparin-binding correlates with increased efficiency of AAV1- and AAV6-mediated transduction of striated muscle, but negatively impacts CNS transduction.

Gene delivery vectors derived from adeno-associated virus (AAV) have great potential as therapeutic agents. rAAV1 and rAAV6, efficiently target striated muscle, but the mechanisms that determine their tropism remain unclear. It is known that AAV6, but not AAV1, interacts with heparin-sulfate proteoglycans (HSPG). HSPGs are not primary receptors for AAV6, but heparin interactions may affect tissue tropism and transduction. To investigate these possibilities, we generated rAAV1 and rAAV6 capsids that do or do not bind heparin. We evaluated the transduction profile of these vectors in vivo across multiple routes of administration, and found that heparin-binding capability influences tissue transduction in striated muscle and neuronal tissues. Heparin-binding capsids transduce striated muscle more efficiently than non-binding capsids, via both intramuscular and intravenous injection. However, rAAV6 achieved greater muscle transduction than the heparin-binding rAAV1 variant, suggesting that there are additional factors that influence differences in transduction efficiency between AAV1 and AAV6. Interestingly, the opposite trend was found when vectors were delivered via intracranial injection. Non-binding vectors achieved robust and widespread gene expression, whereas transduction via heparin-binding serotypes was substantially reduced. These data indicate that heparin-binding capability is an important determinant of transduction that should be considered in the design of rAAV-mediated gene therapies.

Ketamine Relieves Pain at End of Life

Ketamine Relieves Pain at End of Life

Triptans: over the migraine

Migraine is a chronic, recurrent, disabling condition that affects millions of people worldwide. Proper acute care treatment for migraineurs is based on triptans, a class of specific medications approved over 20 years ago. Triptans are serotonin (5-HT1B/1D) receptor agonists that are generally effective, well tolerated and safe. Seven triptans are available worldwide, although not all are available in every country, with multiple routes of administration, giving to doctors and patients a wide choice. Despite the similarities of the available triptans, pharmacological heterogeneity offers slightly different efficacy profiles. Triptans are not pain medications, they are abortive migraine medications which cannot prevent migraines. In addition to migraine attacks, triptans are also helpful for cluster headaches. If they are useful in other primary headaches rather than migraine and cluster headache it is yet to be addressed. In the literature there are only limited controlled clinical data to support a migraine-selective activity for triptans. Reports are available about efficacy of triptans to stop attacks of other types of primary headache, such as tension type headache, hypnic headache and other rare forms of primary headaches. On the other hand, sumatriptan failed to treat the indomethacin-responsive primary headache disorders like chronic paroxysmal hemicrania and hemicrania continua, nor was it effective in the myofascial temporal muscle pain or in atypical facial pain. Why triptans are effective in so different types of primary headaches remain unclear. Up to date, it is not clear whether the antimigrainous activity of the triptans involves an action only in the periphery or in the CNS as well. Probably we should consider triptans as "pain killers" and not only as "migraine killers". We clearly need additional studies on triptans as putative analgesics in well-accepted animal and clinical models of acute and chronic somatic pain.

Getting Big on BPA: Role for BPA in Obesity?

Getting Big on BPA: Role for BPA in Obesity?

Pharmacokinetics of Fluoxetine in Rhesus Macaques following Multiple Routes of Administration

Background/Aims: Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor currently used to treat depression and mood disorders. It has been widely studied clinically and preclinically, yet there is limited knowledge of its pharmacokinetics in nonhuman primates. Methods: The present study characterized the pharmacokinetics of fluoxetine and its active metabolite norfluoxetine in rhesus macaques following both acute (1, 3, 5.6 and 10 mg/kg) and chronic doses (5.6 and 10 mg/kg/day) via different routes of administration (intravenous, subcutaneous, intramuscular, and oral). Blood samples were collected at multiple time points following administration and analyzed using mass spectrometry. Results: Fluoxetine had a half-life of 11–16 h and norfluoxetine had a half-life of 21–29 h. Potentially functionally significant serum concentrations of norfluoxetine were present at 24 h even after a single administration of fluoxetine. Similar to observations in humans under steady state conditions, norfluoxetine accounted for the greater percentage of active drug in the blood stream. Conclusion: A daily dose of 10 mg/kg administered orally maintained serum concentrations in the human clinical range over the course of 6 weeks. Given the long half-lives of fluoxetine and norfluoxetine observed in this study, precautions should be taken when designing preclinical studies to prevent accumulation of drug serum concentrations.

Humanized mice with ectopic artificial liver tissues

"Humanized" mice offer a window into aspects of human physiology that are otherwise inaccessible. The best available methods for liver humanization rely on cell transplantation into immunodeficient mice with liver injury but these methods have not gained widespread use due to the duration and variability of hepatocyte repopulation. In light of the significant progress that has been achieved in clinical cell transplantation through tissue engineering, we sought to develop a humanized mouse model based on the facile and ectopic implantation of a tissue-engineered human liver. These human ectopic artificial livers (HEALs) stabilize the function of cryopreserved primary human hepatocytes through juxtacrine and paracrine signals in polymeric scaffolds. In contrast to current methods, HEALs can be efficiently established in immunocompetent mice with normal liver function. Mice transplanted with HEALs exhibit humanized liver functions persistent for weeks, including synthesis of human proteins, human drug metabolism, drug-drug interaction, and drug-induced liver injury. Here, mice with HEALs are used to predict the disproportionate metabolism and toxicity of "major" human metabolites using multiple routes of administration and monitoring. These advances may enable manufacturing of reproducible in vivo models for diverse drug development and research applications.

Design of a Protective Single-Dose Intranasal Nanoparticle-Based Vaccine Platform for Respiratory Infectious Diseases

Despite the successes provided by vaccination, many challenges still exist with respect to controlling new and re-emerging infectious diseases. Innovative vaccine platforms composed of adaptable adjuvants able to appropriately modulate immune responses, induce long-lived immunity in a single dose, and deliver immunogens in a safe and stable manner via multiple routes of administration are needed. This work describes the development of a novel biodegradable polyanhydride nanoparticle-based vaccine platform administered as a single intranasal dose that induced long-lived protective immunity against respiratory disease caused by Yesinia pestis, the causative agent of pneumonic plague. Relative to the responses induced by the recombinant protein F1-V alone and MPLA-adjuvanted F1-V, the nanoparticle-based vaccination regimen induced an immune response that was characterized by high titer and high avidity IgG1 anti-F1-V antibody that persisted for at least 23 weeks post-vaccination. After challenge, no Y. pestis were recovered from the lungs, livers, or spleens of mice vaccinated with the nanoparticle-based formulation and histopathological appearance of lung, liver, and splenic tissues from these mice post-vaccination was remarkably similar to uninfected control mice.

Sufentanil for chronic pain management

Sufentanil is a highly potent synthetic opioid that is approximately 1000-fold more potent than morphine and up to tenfold more potent than fentanyl. It is most commonly used by anesthesiologists to provide intraoperative analgesia. Although sufentanil is not yet approved for chronic pain management, it is being explored for chronic pain therapy. Owing to its physical properties, high potency, high lipid solubility, high therapeutic index and short duration of action, sufentanil has the potential to provide effective analgesia via multiple routes of administration. The superior pharmacokinetics of sufentanil make it ideal for treatment of breakthrough pain via the sublingual/buccal and nasal routes. Similarly, the transdermal route of sufentanil administration should provide analgesia for a prolonged period. The adverse effects of sufentanil are similar to those of other opioids that are commonly used for chronic pain management (e.g., fentanyl and morphine). Future research is necessary to define the role of sufentanil in the treatment of chronic pain.