Alpha 2-adrenoreceptor Agonists Research Articles

Common peripheral Nerve Block Adjuvants in Combination with Local Anaesthetics

Effective postoperative pain control is crucial. Various techniques are used for this purpose, including continuous nerve blocks, liposomal local anesthetics, and adjuvants added to local anesthetics. While continuous blocks offer advantages, they have challenges and failure rates. Liposomal local anesthetics also have limitations. Adjuvants, categorized as "old" and "new," can extend regional block duration. Epinephrine primarily prolongs local anesthetic effects through localized vasoconstriction. Sodium bicarbonate alkalization benefits specific peripheral nerve blocks but has varying outcomes. Alpha2 adrenoreceptor agonists like clonidine and dexmedetomidine can extend analgesia but may lead to side effects through systemic absorption. Opioid agonists such as buprenorphine and tramadol yield variable results depending on the surgical type, with potential benefits through intravenous or intramuscular administration. The review further emphasizes the significance of adjuvants like corticosteroids and NMDA (N-Methyl-D-Aspartate) receptor antagonist magnesium sulfate in consistently prolonging analgesia when combined with local anesthetics. The comprehensive analysis of peripheral nerve block adjuvants provides valuable insights for healthcare practitioners to navigate this dynamic field and optimize pain management strategies. It underscores the evolving landscape and the necessity of considering patient-specific factors, surgical context, and available evidence in the selection of adjuvants. The call for further research highlights the ongoing efforts to refine the use of adjuvants for safe and effective postoperative pain management.

Effect of oral clonidine and tizanidine on the induction dose of propofol and intubation response in general anesthesia

Background: Laryngoscopy and tracheal intubation are associated with hemodynamic and cardiovascular responses consisting of increased heart rate, blood pressure and tachycardia and dysarrhythmias. The alpha2-adrenoreceptor agonists such as clonidine and tizanidine have several beneficial actions during the perioperative period. They improve hemodynamic stability in response to endotracheal intubation and surgical stress. Objective: To study the effect of oral clonidine and tizanidine on induction dose of propofol and hemodynamic responses after laryngoscopy in patients undergoing surgery under general anesthesia Methods: Hundred patients in age group of 18-70 years old of ASA 1/2 undergoing elective surgeries under general anesthesia with tracheal intubation was included in the study. Tizanidine 4 mg prescribed to group A, 0.1 mg clonidine to group B 60 min before the time of induction or laryngoscopy. systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate recorded before induction, pre-intubation, after intubation at 0 min, and then at interval of 1,3,5 minute after laryngoscopy by an independent observer.

A prospective, randomized controlled, double-blinded study comparing dexmedetomidine and clonidine as an adjuvant to ropivacaine in femoral nerve block for postoperative analgesia in patients undergoing total knee arthroplasty

BackgroundTotal knee arthroplasty (TKA) causes significant postoperative pain, imposing a limitation on postoperative mobilization crucial in regaining joint function. Ultrasound (US)-guided femoral nerve block (FNB) in complex knee surgeries is associated with better pain scores and fewer hospital admissions. Alpha-2 (α2) adrenoreceptor agonists have been the recent focus of interest as additives to local anesthetic. We aimed to compare the equivalent dose of dexmedetomidine and clonidine as an adjuvant to ropivacaine in US-guided FNB in TKA. A prospective, randomized, controlled, double-blinded study was conducted involving 80 American Society of Anesthesiologists’ physical status (ASA-PS) I, II, and III patients scheduled to undergo TKA under subarachnoid block. Group 1 (n = 40) patients received 1 μg/kg dexmedetomidine and group 2 (n = 40) patients with 1 μg/kg clonidine as adjuvants added to 20 ml of 0.75% ropivacaine. Duration of postoperative analgesia, pain scores, sedation scores, hemodynamics, rescue analgesia requirement, complications, and patient satisfaction were compared.ResultsThe total duration of analgesia in group 1 was better compared to group 2 (p < 0.001).The patients were better sedated and the mean NRS scores were significantly lower (p < 0.05) in group 1 up to 24 h postoperatively. Total analgesic consumption was reduced in group 1, with a p value < 0.001. Patient satisfaction was significantly better (p < 0.001) in group 1 compared to group 2.ConclusionWe conclude that dexmedetomidine added as an adjuvant in FNB increased the duration of analgesia when compared to clonidine with decreased NRS scores, reduced postoperative tramadol requirement, and better sedation and patient satisfaction.Trial registrationResearchregistry6709, “Retrospectively registered” on 31 March 2021.

Variability of response to pharmacotherapy of naltrexone and guanfacin in patients with opioid dependence syndrome: pharmacogenetic aspect

There is a problem of insufficient effectiveness of pharmacotherapy for the relapse prevention in patients with opioid dependence. In Russian Federation naltrexone is a mainly used medication for treatment of opioid addiction. However, it has no effects on stress, craving, and impulsiveness. Alpha-2 adrenoreceptor agonists can reduce the severity of these symptoms and thus might improve effectiveness of naltrexone treatment. Pharmacogenetic analysis is useful for determining potential responders and nonresponders to the treatment of opioid dependence. The aim of this study was to evaluate the variability of response to pharmacotherapy of naltrexone and guanfacin in patients with opioid dependence syndrome. This was a multicenter, randomized, double-blind, placebo-controlled clinical trial using a pharmacogenetic approach. The good tolerability and safety of naltrexone and guanfacine combination with long-term course treatment for stabilization of remission of opioid dependence was scientifically substantiated. Was showed a moderate stress-protective and anti-craving effect of guanfacin in the period of early remission with opioid dependence syndrome. Genetic analysis is useful for determining potential responders to the treatment of opioid dependence, genotyping can increase effectiveness of pharmacotherapy.

Intraoperative anaesthetic complications in dogs undergoing general anaesthesia for thoracolumbar hemilaminectomy: a retrospective analysis

ObjectiveTo establish the incidence of intraoperative anaesthetic complications in dogs undergoing general anaesthesia (GA) for thoracolumbar hemilaminectomy (TH), to determine whether GA duration affects incidence of intraoperative complications and to identify associations between intraoperative complications. Study designRetrospective observational study. AnimalsA total of 224 client-owned dogs of various breeds undergoing TH for intervertebral disc extrusion. MethodsAnaesthetic records of dogs undergoing TH at a university teaching hospital between 2010 and 2016 were analysed. Data recorded included breed, sex, body weight, GA duration, magnetic resonance imaging (MRI) under the same GA, pharmacological intervention to increase heart rate (PIHR), hypotension (mean arterial blood pressure < 60 mmHg for ≥ 10 minutes), mechanical ventilation (MV) for inadequate ventilation, hypothermia (oesophageal temperature < 37 °C), oesophageal temperature ≥ 39 °C (T ≥ 39 °C), temperature trend, regurgitation and use of alpha-2 adrenoreceptor agonists, acepromazine, ketamine or lidocaine. Multivariate logistic regression models were fitted for hypothermia, T ≥ 39 °C, hypotension and PIHR with forced inclusion of GA duration. ResultsHypothermia was the most common complication (63.8% incidence), followed by MV implementation (63.4%), hypotension (33.9%), PIHR (24.6%), T ≥ 39 °C (20.5%) and regurgitation (4.9%). Multivariate models revealed that MRI and hypotension were associated with an increased risk of hypothermia, whilst increasing body weight, alpha-2 adrenoreceptor agonists and MV were associated with a reduced risk. Alpha-2 adrenoreceptor agonists and GA duration were associated with an increased risk of T ≥ 39 °C, whilst hypotension was associated with a reduced risk. Hypothermia and PIHR were associated with an increased risk of hypotension, whereas increased body weight was associated with a reduced risk. MV and hypothermia were associated with an increased risk of PIHR, whereas increased body weight was associated with a reduced risk. Conclusions and clinical relevanceIncreasing GA duration was associated with increased risk of T ≥ 39 °C, but not any other intraoperative complications.

Veterinary and Human Anaesthesia: An Overview of Some Parallels and Contrasts

The history of human and veterinary anaesthesia is both intertwined and parallel. Physicians and anaesthetists often first experimented on animals and developments from human anaesthesia have been incorporated into veterinary medicine. Within veterinary medicine, anaesthesia is a specialty discipline as it is in human medicine. Veterinary anaesthetists undertake additional training and rigorous examinations for a diploma or fellowship. In contrast to human anaesthesia in Australia and New Zealand, veterinary anaesthesia is often performed by non-specialists and by veterinary nurses. Veterinary anaesthesia uses many of the same drugs for premedication, induction and maintenance of anaesthesia as human anaesthesia. However, there are species specific effects of some of the drugs used that differ from the effects in humans. Furthermore, some agents, particularly alpha-2 adrenoreceptor agonists and ketamine, are used very widely in veterinary practice. Also in contrast to most human anaesthesia, in large animal and exotic animal practice the patients can present a physical danger to the anaesthetist. The most notable contrast between human and veterinary anaesthesia is in the reported perioperative complication and mortality rates, with a species dependent perianaesthetic mortality of up to 2% in dogs, cats and horses and greater than 2% in guinea pigs and birds, which is up to 100-fold higher than in human anaesthesia.

Opioid‐Free Perioperative Analgesia for Hemicolectomy in a Patient With Opioid‐Induced Delirium: A Case Report and Review of the Analgesic Efficacy of the Alpha‐2 Agonist Agents

Surgical pain in patients with documented opioid-induced delirium can be difficult to treat. We present a case of a patient undergoing laparoscopic hemicolectomy effectively treated with an opioid-free, alpha-2 adrenoreceptor agonist analgesic regimen. A 21-year-old woman with persistent abdominal pain presented to the operating room for laparoscopic hemicolectomy for redundant right colon. Her medical history included a recently diagnosed postoperative opioid-induced delirium. Epidural infusion with local anesthetic offered partial pain relief with sensory levels of T9-L2. With the addition of dexmedetomidine infusion in the immediate postoperative period, the patient was comfortable with pain scores of 1 to 2/10 on Numerical Rating Scale (NRS). On postoperative day 1, the infusion was discontinued and the clonidine, 12 μg/hours was added to the epidural bupivacaine. With increased sedation 48 hours later, neuraxial clonidine was discontinued in favor to transdermal clonidine 0.1 mg/week, which was maintained until hospital discharge. Pain scores were maintained at 2 to 3/10 on NRS for the next 3 days when increased abdominal distention because of abscess formation rendered a new surgical intervention. The analgesia for the exploratory laparoscopy was maintained using epidural clonidine and bupivacaine infusion as well as intravenous dexmedetomidine, which were maintained another 2 days. Pain scores remained minimal until discharged home 3 day later. Nonopioid analgesic regimens are beneficial in patients at risk of postoperative cognitive dysfunction attributable to opioids. Successful postoperative analgesia was achieved in our patient by alternating various routes of administration of alpha-2 adrenoreceptor agonists.

Dexmedetomidine and Clonidine Inhibit Ventricular Tachyarrhythmias in a Rabbit Model of Acquired Long QT Syndrome

Agents with α-2 adrenoreceptor (AR) agonistic action have reportedly suppressed tachyarrhythmias. We hypothesized that α-2 AR agonists would have an inhibitory effect on abnormal repolarization-related ventricular tachyarrhythmias (VTs). To test this hypothesis, the effects of 2 clinically available α-2 AR agonists (dexmedetomidine and clonidine) on the occurrence of VTs were assessed in a methoxamine-sensitized rabbit model of acquired long QT syndrome (Study 1: n=45). In control rabbits, administration of methoxamine and nifekalant almost invariably caused VTs (14/15). In contrast, incidence of VT significantly decreased during the treatment with dexmedetomidine (1μg·kg(-1)·min(-1): 5/12 [P<0.01 vs. control]) or with clonidine (33.3μg·kg(-1)·min(-1): 10/18 [P<0.01]). To verify that VTs in this animal model are triggered by early afterdepolarization (EAD), the monophasic action potential on the left ventricular surface was recorded in 28 open-chest rabbits (Study 2). EAD-like hump was less frequently detected during treatment with clonidine or dexmedetomidine (2/14) than in saline-treated rabbits (9/10, P<0.005). Presence of a hump was significantly related to the advent of VTs (P<0.05). Agents with α-2 AR agonistic action have an inhibitory effect on VTs in a rabbit model of long QT syndrome. Alpha-2 AR agonists, especially dexmedetomidine, may be a therapeutic choice for abnormal repolarization-related VTs that are resistant to conventional treatment.

Effects of Alpha 1- and Alpha 2-Adrenoreceptor Stimulation on Galanin mRNA Expression in Primary Cultured Superior Cervical Ganglion Neurons

Galanin (Gal) is a 29-amino-acid neuropeptide which is expressed in superior cervical ganglion (SCG) neurons and plays a trophic role in the adult animal and acts as an inhibitory modulator of cholinergic and noradrenergic neurotransmission. Whether activation or inhibition of alpha-adrenoreceptors infl uences Gal mRNA expression in SCG neurons remains unknown. Here, we have evaluated the possible regulation of Gal mRNA expression with acute (4 h) and chronic (4 days) stimulation of alpha 1- and alpha 2-adrenoreceptor agonists or antagonists in primary cultured SCG neurons. The results showed that the amount of Gal mRNA expression in cultured SCG neurons increased signifi cantly after chronic stimulation with alpha 2-adrenoreceptor antagonist yohimbine compared with control SCG neurons at the same time point, whereas the amount of Gal mRNA expression decreased signifi cantly after chronic stimulation with alpha 2-adrenoreceptor agonist clonidine as compared with that in control group. All these effects were not dose-dependent on the administration of alpha 2-adrenoreceptor agonist clonidine or alpha 2-adrenoreceptor antagonist yohimbine. Alpha 1-adrenoreceptor agonist phenylephrine or antagonist prazosin chronic stimulation did not have effects on Gal mRNA expression. Acute exposure of these agents did not have effects on Gal mRNA expression. The present study showed that Gal may be regulated by activation or inhibition of alpha 2-adrenoreceptors, but not alpha 1-adrenoreceptors in sympathetic neurons.

Adrenergic Regulation of Vasomotor Responses in Skeletal Muscle Composed of Different Fiber Types

The sympathetic nervous system (SNS) has a profound ability to control blood flow and vascular resistance in skeletal muscle at rest and during exercise. The purpose of this study was to further elucidate the influence of the SNS on vasoconstrictor tone in muscles composed of different fiber types. Blood flow to the red (RGast) and white (WGast) portions of the gastrocnemius and the soleus muscles were measured pre‐ and post‐denervation, and dose‐response relations to alpha1 (phenylephrine) or alpha2 (clonidine) adrenoreceptor agonists were determined in isolated arterioles from these muscles. Denervation increased blood flow 8.7‐fold in the fast low‐oxidative muscle WGast while only eliciting an ∼2.7‐fold increase in the slow oxidative (soleus) and fast oxidative (RGast ) muscles. In arterioles, sensitivity to phenylephrine was greater in WGast and RGast versus the soleus muscle, whereas vasoconstriction to clonidine was greater in WGast (~50%) relative to that in RGast (~31%) and soleus (~17%). These data indicate 1) an intermediate control of vascular resistance by the SNS in fast oxidative muscle versus the other muscle types, and 2) the SNS influence on blood flow could fully account for the magnitude of the hyperemia observed during exercise in fast low‐oxidative muscle.

The alleviation of pain in cattle: a review.

Abstract The alleviation of pain in cattle is dependent on the ability to recognise pain and to determine whether systemic analgesia or local anaesthesia is effective. Local and regional anaesthesia have long been used to reduce pain and its attendant behaviours during surgery in conscious cattle, but concern about post-operative pain and its alleviation are more recent developments. A number of classes of analgesics (opioids, non-steroidal anti-inflammatory drugs (NSAIDs), alpha-2 adrenoreceptor agonists) are used in cattle to alleviate pain caused by surgery, injury or disease. These drugs can be useful analgesics, but their use is limited by concern about residues and cost. The NSAID, ketoprofen, has been shown to be an effective analgesic after dehorning and castration when combined with local anaesthesia in calves. Xylazine is also an effective analgesic but there is very limited information on the analgesic effects in cattle of many other drugs. There are a limited number of drugs registered for use in cattle and it is important that local anaesthetics and systemic analgesics are available to alleviate pain in this species at prices which make them economically attractive.

Hemodynamic effects of clonidine outweigh potential neuroprotective effects in experimental stroke

Introduction: There are various publications reporting neuroprotective effects of alpha2-adrenoreceptor agonists, such as clonidine and dexmedetomidine, both in animal studies and in vitro. We have studied the effects of clonidine and the role of different alpha2-adrenoreceptor subtypes in an experimental stroke model using transgenic mice with deletions of alpha2-receptor subtypes.

Clonidine increases membrane-associated phospholipase A2

An anti-inflammatory effect of alpha2-adrenoreceptor agonists has been suggested. Phospholipase A2 is a key enzyme in the production of precursors of inflammatory lipid mediators. The aim of the present study was to investigate the effect of clonidine on phospholipase A2 activity in an established in vitro model. Human being platelet membranes containing active phospholipase A2 were exposed to buffer control or to three increasing concentrations of clonidine. Phospholipase A2 was measured by a radioisotope technique. A massive increase in phospholipase A2 activity was measured after clonidine exposure leading to final values of 92.5 +/- 3.1 pmol mg protein(-1) min(-1) (4.5-fold higher than control values; P < or = 0.01 vs. control). After clonidine exposure the maximal reaction velocity increased, while the Michaelis-Menten constant did not change. The Lineweaver-Burk representation suggested an interaction of clonidine with the phospholipase A2-substrate complex as well as the phospholipase A2 molecule. We conclude that the putative anti-inflammatory effect of clonidine was not caused by inhibition of phospholipase A2.

T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure

Acute or chronic glaucoma is often associated with an increase in intraocular pressure (IOP). In many patients, however, therapeutic pressure reduction does not halt disease progression. Neuroprotection has been proposed as a complementary therapeutic approach. We previously demonstrated effective T-cell-based neuroprotection in experimental animals vaccinated with the synthetic copolymer glatiramer acetate (copolymer-1, Cop-1), a weak agonist of self-antigens. This study was undertaken to test different routes and modes of vaccination with Cop-1 as treatment modalities for protection against retinal ganglion cell (RGC) death caused by chronic elevation of IOP in rats, and to determine whether anatomical neuroprotection is accompanied by functional neuroprotection. In a chronic model of unilaterally high IOP, Cop-1 vaccination, with or without an adjuvant, protected rats against IOP-induced loss of RGCs by eliciting a systemic T-cell-mediated response capable of cross-reacting with self-antigens residing in the eye. In rats deprived of T cells, Cop-1 (unlike treatment with alpha2-adrenoreceptor agonists) was not protective of RGCs, substantiating the contention that its beneficial effect is not conferred directly but is T-cell-mediated. Pattern electroretinography provided evidence of functional protection. Thus, vaccination with adjuvant-free Cop-1 can protect RGCs from the consequences of elevated IOP in rats. This protection is manifested both morphologically and functionally. These findings can be readily implemented for the development of a therapeutic vaccination to arrest the progression of glaucoma.

Alpha-2 agonists in neuroanesthesia

La dexmedetomidina se usó para sedación inicialmente en unidades de cuidados intensivos. Sin embargo, sus efectos sedantes, analgésicos y ansiolíticos sin alteración de la función ventilatoria, permiten ampliar su uso en cirugía como anestésico intravenoso. La literatura reporta su utilidad en poblaciones quirúrgicas definidas, pero aún faltan estudios que respalden su utilización en todos los escenarios de la anestesia total intravenosa (TIVA). El propósito de la actual revisión es describir el papel de la dexmedetomidina en la misma.Se realizó la búsqueda de literatura en las bases de datos referenciales de PubMed, Medline, EMBASE, Cochrane y LILACS. Fue ampliada según la bibliografía encontrada en los artículos inicialmente revisados y analizadosDexmedetomidine was used initially for sedation in intensive care units. However, because of its sedative, analgesic and anti-anxiety effects and the fact that it does not alter ventilatory function, its use may be expanded as an intravenous agent in surgery. There are reports in the literature about its effective use in specific surgical populations, although further studies are required in order to support its use in all situations where total intravenous anesthesia (TIVA) is applied. The purpose of this review is to describe the role of dexmedetomidine in this form of anesthesia.A literature search was conducted in PubMed, Medline, EMBASE, Cochrane and LILACS. The search was expanded based on the references found in the articles repor los autores; la búsqueda fue hecha bajo los términos MeSH incluidos en las palabras claves.

Drugs used in the treatment of opioid tolerance and physical dependence: a review.

Opioid drugs used in the treatment of severe pain are known to produce tolerance that requires a dose increase to maintain a sufficient analgesic effect. As this is connected with side effects such as respiratory depression, it is highly desirable to avoid or at least attenuate the development of tolerance. Closely related, but in some respect dissociable, is the phenomenon of physical dependence, which becomes apparent particularly in heroin withdrawal. Our knowledge about the mechanisms underlying tolerance has increased dramatically in recent years, but a final picture of the importance of each particular mechanism under in vivo conditions has not yet emerged. Recent studies suggest that the so-called receptor down-regulation is not the main mechanism in vivo. A desensitization on the basis of receptor decoupling, receptor internalization and increased alternative coupling to stimulatory G-proteins have been demonstrated. However, a functional antagonism of the opioid effects seems to be clinically most important, mediated by the activation of NMDA receptors, up-regulation of adenylyl cyclase and nitric oxide synthase. Drugs blocking these mechanisms are the most promising option in the treatment of tolerance. Namely, alpha2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan have been used to minimize tolerance development during opioid treatment. Moreover, clinical strategies such as opioid rotation and multimodal analgesia, i.e. the simultaneous application of several analgetics of different type, have proven to be successful approaches.

Hypertension artérielle et anesthésie

Hypertension is one of the most important risk factors for cerebrovascular disease and ischaemic heart disease. Postoperative adverse outcomes of hypertension include cardiac death, left ventricular hypertrophy (with impaired diastolic function) leading to ventricular failure, myocardial ischaemia and infarction, renal damage and cerebrovascular accidents. The role of the anaesthetist for patients suffering from chronic hypertension goes beyond that in most other patient population since there is a unique opportunity to improve long-term survival and function by applying adequate preoperative evaluation and refined perioperative anaesthetic management. Maintenance of hemodynamic stability throughout the perioperative period is essential in these patients with cardiovascular risk, most of whom benefit from cardiac treatments designed to improve both their symptoms and life expectancy. Anesthetic agents development and improved delivery have reduced the importance of direct anaesthetic effects on heart versus effects of interactions with other cardio-vascular drugs. In patients with hypertensive disease undergoing anaesthesia and surgery, disease-drug-anaesthesia interaction may either increase or reduce the likelihood of perioperative morbidity and mortality. The blockade of the sympathetic system is well tolerated and has several beneficial effects including the prevention of hypertensive episodes and myocardial ischemia. By contrast, the blockade of the renin-angiotensin system markedly increases the lowering blood pressure effect of anesthesia. This is not surprising if one takes into account that this system is activated by any decrease in the loading conditions of the heart, especially preload. That leads to withdraw treatments, which interfere with the renin angiotensin system, the eve of surgery. Better knowledge of the physiopathological mechanisms involved in postoperative complications now enables to define perioperative managements for hypertensive patients undergoing non cardiac surgery and thus limit the risk of anesthesia. The main goal of the perioperative management is to limit postoperative stress by adequate intra and postoperative management and to control postoperatively increased sympathetic tone or its circulatory effects by administering preventive cardiovascular medications which interfere with the sympathic system. The prevention of intraoperative hypothermia and intensive postoperative analgesia significantly limit circulatory stress in the postoperative period. However, although diminished, these contraints have not been abolished. This is the reason why many authors have envisaged the administration of cardiovascular medication to effectively limit the sympathetic stimulation which persists several days after surgery. Two types of cardiovascular drugs have been recommended : beta-adrenergic blocking drugs and alpha-2 adrenoreceptor agonists. Postoperative hypertension episodes must be treated by vasodilatators (calcium channel blockers) and/or betablockers.

Role of sensory nervous system vasoactive peptides in hypertension.

The goal of the present research was to elucidate the roles and mechanisms by which the sensory nervous system, through the actions of potent vasodilator neuropeptides, regulates cardiovascular function in both the normal state and in the pathophysiology of hypertension. The animal models of acquired hypertension studied were deoxycorticosterone-salt (DOC-salt), subtotal nephrectomy-salt (SN-salt), and Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertension during pregnancy in rats. The genetic model was the spontaneously hypertensive rat (SHR). Calcitonin gene-related peptide (CGRP) and substance P (SP) are potent vasodilating neuropeptides. In the acquired models of hypertension, CGRP and SP play compensatory roles to buffer the blood pressure (BP) increase. Their synthesis and release are increased in the DOC-salt model but not in the SN-salt model. This suggests that the mechanism by which both models lower BP in SN-salt rats is by increased vascular sensitivity. CGRP functions in a similar manner in the L-NAME model. In the SHR, synthesis of CGRP and SP is decreased. This could contribute to the BP elevation in this model. The CGRP gene knockout mouse has increased baseline mean arterial pressure. The long-term synthesis and release of CGRP is increased by nerve growth factor, bradykinin, and prostaglandins and is decreased by alpha2-adrenoreceptor agonists and glucocorticoids. In several animal models, sensory nervous system vasoactive peptides play a role in chronic BP elevation. In the acquired models, they play a compensatory role. In the genetic model, their decreased levels may contribute to the elevated BP. The roles of CGRP and SP in human hypertension are yet to be clarified.

Drug Interactions with Patient-Controlled Analgesia

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems. Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of alpha1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance. Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or alpha2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.

Spinal drug delivery.

Clinicians currently base decisions regarding the use of intrathecal drug therapy for chronic pain on reports from uncontrolled and retrospective studies that fail to rely on standardized outcome measures. In this article, we summarize what is known about currently administered intrathecal therapies, including opioids, gamma-aminobutyric acid agonists, alpha-2 adrenoreceptor agonists, local anesthetics (sodium channel antagonists), calcium channel antagonists, miscellaneous agents, and drug combination therapy. In addition, we offer a brief look at novel approaches that may revolutionize intrathecal drug delivery.