Low Dose Of Baclofen Research Articles

Long-term results on the suppression of secondary brain injury by early administered low-dose baclofen in a traumatic brain injury mouse model

Secondary injury from traumatic brain injury (TBI) perpetuates cerebral damages through varied ways. Attenuating neuroinflammation, which is a key feature of TBI, is important for long-term prognosis of its patients. Baclofen, a muscle relaxant, has shown promise in reducing excessive inflammation in other neurologic disorders. However, its effectiveness in TBI remains ambiguous. Thus, our study aimed to investigate whether early administration of baclofen could elicit potential therapeutic effects by diminishing exaggerated neuroinflammation in TBI mice. In this study, 80 C57BL/6 mice were used, of which 69 mice received controlled cortical impact. The mice were divided into six groups (11–16 mice each). Baclofen, administered at dose of 0.05, 0.2 and 1 mg/kg, was injected intraperitoneally a day after TBI for 3 consecutive weeks. 3 weeks after completing the treatments, the mice were assessed histologically. The results showed that mice treated with baclofen exhibited a significantly lower volume of lesion tissue than TBI mice with normal saline. Baclofen also reduced activated glial cells with neurotoxic immune molecules and inhibited apoptotic cells. Significant recovery was observed and sustained for 6 weeks at the 0.2 mg/kg dose in the modified neurological severity score. Furthermore, memory impairment was recovered with low-doses of baclofen in the Y-maze. Our findings demonstrate that early administration of low dose baclofen can regulate neuroinflammation, prevent cell death, and improve TBI motor and cognitive abnormalities.

Serial electroencephalography changes in low-dose baclofen intoxication.

Serial electroencephalography changes in low-dose baclofen intoxication.

Management of Central Hyperthermia in Traumatic Brain Injury Using Baclofen

Central hyperthermia in cases of traumatic brain injury (TBI) is often misdiagnosed or underdiagnosed due to inadequate data. The current diagnosis is one of exclusion. Existing treatment as per guidelines is symptomatic and supportive. Continuous fever after TBI may delay therapy, worsen functional outcome and prolong hospital stay. We discuss a case of a 33-year-old gentleman with TBI with recurring fever spikes during inpatient rehabilitation, non-responsive to antipyretics and antibiotics. A diagnosis of central hyperthermia was reached after eliminating other possible causes. Based on a prior case report, baclofen was tried successfully to manage central hyperthermia. In our patient, a complete cessation of fever was noted within 2 days of initiation of baclofen. To test the effect and minimise the possibility of coincidental dissipation of fever, baclofen was temporarily withdrawn. The corresponding decrease in temperatures and days of baclofen administration followed by recurrence with cessation, are depicted graphically. Once baclofen was resumed, he remained afebrile for the remainder of his inpatient period. This case brings to light the possible efficacy of low-dose baclofen in the management of fever of central origin. It also highlights the importance of considering the possibility of fever of central origin in the subacute stage after TBI. Standardisation of baclofen use with well-designed clinical trials is the proposed next step.

A single, clinically relevant dose of the GABAB agonist baclofen impairs visuomotor learning.

The GABAB agonist baclofen is taken daily as a treatment for spasticity by millions of stroke, brain injury and multiple sclerosis patients, many of whom are also undergoing motor rehabilitation. However, decreases in GABA are suggested to be a key feature of human motor learning, which raises questions about whether drugs increasing GABAergic activity may impair motor learning and rehabilitation. In this double-blind, placebo-controlled study, we investigated whether a single 10 mg dose of the GABAB agonist baclofen impaired motor sequence learning and visuomotor learning in 20 young healthy participants of both sexes. Participants trained on visuomotor and sequence learning tasks using their right hand. Transcranial magnetic stimulation (TMS) measures of corticospinal excitability, GABAA (short-interval intracortical inhibition, 2.5 ms) and GABAB (long-interval intracortical inhibition, 150 ms) receptor activation were recorded from left M1. Behaviourally, baclofen caused a significant reduction of visuomotor aftereffect (F 1,137.8 = 6.133, P = 0.014) and retention (F 1,130.7 = 4.138, P = 0.044), with no significant changes to sequence learning. There were no overall changes to TMS measured GABAergic inhibition with this low dose of baclofen. This result confirms the causal importance of GABAB inhibition in mediating visuomotor learning and suggests that chronic baclofen use could negatively impact aspects of motor rehabilitation.

Clinical Predictors of Response to Baclofen in the Treatment of Alcohol use Disorder: Results from the BacALD Trial.

To examine clinical predictors of treatment response to baclofen in patients with alcohol use disorder (AUD). Data from a randomised controlled trial (RCT) (N = 104), in which AUD patients received placebo or baclofen (30 mg/day or 75 mg/day) for 12 weeks, were analysed to determine predictive effects of the following four clinical characteristics: alcoholic liver disease (ALD), baseline alcohol consumption, craving and anxiety. Treatment outcomes included: (i) time to lapse and (ii) time to relapse. For both outcome measures, baclofen, irrespective of dose, was more effective when alcohol consumption was higher at baseline. Relative to placebo, baclofen increased time to first lapse in patients with higher baseline alcohol consumption (HR = 0.459, 95% CI = 0.219-0.962, P < 0.05). Similarly, baclofen increased time to first relapse in patients with higher alcohol consumption at baseline (HR = 0.360, 95% CI = 0.168-0.772, P < 0.05). There were no predictive effects of other baseline characteristics on time to lapse nor time to relapse. Directly comparing high dose of baclofen (75 mg/day) with low dose of baclofen (30 mg/day) revealed no differences with regards to predictors of baclofen response. Baclofen, relative to placebo, was more effective when alcohol consumption was higher at baseline.

The dosage and administration of long-term intrathecal baclofen therapy for severe spasticity of spinal origin.

Retrospective chart audit. To indicate the appropriate baclofen dosage to control severe spasticity of spinal origin and to develop the optimal administration protocol for long-term intrathecal baclofen (ITB) therapy. Department of Orthopaedic Surgery, Spinal Injuries Center, Japan. Thirty-four people with spasticity of various spinal origins who were consistently treated at our hospital were included. The median follow-up period was 6 years and 11 months. Measures of Ashworth score were taken before and after surgical implant of baclofen pump. We decided not to increase the baclofen dosage after the Ashworth score reached 1. We recorded the control of spasticity, changes in the baclofen dose, and the incidence of complications. The average Ashworth score was 3.31 (1.75-4.0) before implant surgery, 1.38 (1.0-2.25) after implant surgery, and 1.39 (1.0-2.25) at the final follow-up, while the average baclofen dose (therapeutic/optimal dose) was 230.6 μg/day (50-450). The incidence of each complication was as follows: 8.8% (n = 3) catheter-related, 2.9% (n = 1) pump-related and 5.9% (n = 2) drug tolerance. No patients experienced withdrawal syndrome. Dose fluctuation with changes in the pathology of the original disease was observed in three cases. The usage of the Ashworth score as a guide for dose adjustment was found to be a good objective indicator for ITB therapy. The administration based on this objective indicator made it possible to effectively manage patients with a relatively low dose of baclofen and a low rate of drug-related complications.

Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30–60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ2=0.41; p=0.813) or the 16-weeks complete medication period (χ2=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.

English

Baclofen has been commonly used for the treatment of various neurological disorders. Because of its ability to suppress alcohol consumption and craving, it has now been introduced in the treatment of alcohol dependence. Baclofen-induced skin rashes are extremely rare, especially morbiliform rashes. We report a case, who developed morbiliform rashes with a low dose of baclofen.

Dose-dependent Changes in Gait Pattern after Intrathecal Baclofen Bolus Injection in Adult Ambulatory Cerebral Palsy: A Case Report

Intrathecal baclofen (ITB) therapy has been proven to reduce severe spasticity in cerebral palsy (CP). However, few results reported the objective gait pattern change after ITB bolus injection in adult ambulatory CP. We therefore evaluated observational and kinematic gait patterns at different ITB bolus injection doses. We performed a test trial of 3-day ITB bolus injections at doses of 12.5 μg, 25 μg, and 50 μg in ambulatory CP. We evaluated modified Ashworth scale, visual analogue scale, observational gait scale, and kinematic gait analysis after ITB bolus injection. Intrathecal administration of low-dose baclofen 25 μg was successfully used not only for the treatment of spasticity but also for the treatment of gait disturbance, whereas the higher dose baclofen 50 μg induced foot drop and deteriorated gait pattern. We experienced dose-dependent changes in gait pattern confirmed by the observational and kinematic gait assessments after ITB bolus injection in adult ambulatory CP. (Brain & NeuroRehabilitation 2015; 8: 104-108)

Low-dose baclofen therapy raised plasma insulin-like growth factor-1 concentrations, but not into the normal range in a predictable and sustained manner in men with chronic spinal cord injury

ObjectiveTo evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. <250 ng/ml).DesignProspective, open-label, dose titration study. Baclofen was administered at 20 mg/day for 8 weeks; then increased to 40 mg/day for another 8 weeks. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study.ResultsThe subjects were 43 ± 12 years old, had duration of injury of 20 ± 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 ± 63 vs. 217 ± 69 ng/ml; P < 0.05), weeks 8 and 10 (188 ± 95 vs. 228 ± 93 ng/ml; P < 0.05), and weeks 8 and 16 (188 ± 95 vs. 259 ± 92 ng/ml; P < 0.05). No serious side effects were observed at 20 mg/day; the 40 mg/day dose was less well tolerated.ConclusionBaclofen was not effective at sustaining plasma IGF-1 concentrations in the physiological range in men with chronic SCI.

Successful Treatment of Intractable Low Back and Pelvic Pain Caused by Advanced Prostate Cancer with Intrathecal Clonidine and Baclofen Infusion

Background: Intrathecal opioid infusion therapy has been increasingly utilized in patients with severe malignant and nonmalignant pain syndromes in the past few decades. By infusing small amount of analgesics directly into the cerebrospinal fluid (CSF) in close proximity to the receptor site in the spinal cord, spinally mediated analgesia may be achieved while sparing some of the side effects due to systemic opioids. Traditionally, the most commonly infused analgesic for intrathecal infusion is an opioid. Morphine represents the only FDA-approved opioid for intrathecal administration, although other opioids may also be used off-label. However, in patients who have demonstrated intolerance to oral opioid(s), alternative analgesics may be tried to achieve satisfactory analgesia. Objective: To present a case report of a 73-year old male with intractable low back and pelvic pain due to invasive prostate cancer, unable to tolerate any opioid, being successfully treated by intrathecal infusion of clonidine and baclofen. Case Report: A 73-year-old male with intractable low back pain and pelvic pain due to invasive prostate cancer was referred to our clinic for pain management. The patient had undergone hormonal therapy, radiation therapy, radical prostectomy, and rectal resection. Trial of non-opioid analgesics was unsuccessful in controlling his pain. Multiple opioids trials were complicated by persistent nausea and vomiting. Other interventional techniques were attempted, but only offered short-term efficacy. Intraspinal drug delivery (IDD) therapy was considered and attempted. Considering his intolerance to various oral opioids despite meticulous opioid dose titration, an outpatient continuous epidural infusion of clonidine was conducted, which provided satisfactory analgesia. The patient subsequently underwent permanent IDD pump placement. Results: The intrathecal infusion of clonidine was initiated at 50 mcg/day. Over the following 4 months, the dosage was gradually titrated up to 350 mcg/day, with satisfactory pain relief. However, he did report frequent drowsiness during daytime, which was felt to be due to intrathecal clonidine. The decision to add low dose baclofen to the intrathecal infusion and simultaneously lower the clonidine dose was made. The intrathecal regimen was changed to clonidine 150 mcg/day and baclofen 50 mcg/day. His daytime sleepiness improved significantly and his pain control remained satisfactory. Over the following 3 months, his intrathecal regimen was further titrated to clonidine 200 mcg/day and baclofen 100mcg/day. He remained on this regimen for over 12 months with satisfactory pain relief and without experiencing excessive sedation. Addition of baclofen to intrathecal clonidine infusion led to improved analgesia without affecting his alertness, probably via a synergistic mechanism. Conclusion: Under certain circumstance when intrathecal opioid infusion cannot be tolerated, intrathecal clonidine and baclofen may be used as alternatives to provide spinally mediated antinociception.

Treating alcohol withdrawal with oral baclofen: A randomized, double‐blind, placebo‐controlled trial

Abrupt cessation of alcohol intake causes habituated drinkers to experience symptoms of alcohol withdrawal syndrome (AWS). To determine the effect of the gamma-aminobutyric acid (GABA)-B agonist baclofen on the course of acute symptomatic AWS. Prospective, randomized, double-blind, placebo-controlled clinical study. Two tertiary-care hospitals in Duluth, Minnesota. Inpatient adults admitted for any reason (including AWS) judged to be at high risk for AWS. Inpatients who developed symptoms of AWS received symptom-triggered benzodiazepine treatment using lorazepam by standard protocol, and were randomized to receive baclofen 10 mg or placebo, 3 times per day, orally. AWS severity was assessed using the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar); lorazepam dose was monitored. Seventy-nine subjects were enrolled. The 44 subjects who developed symptoms of AWS were randomized to baclofen or placebo. Thirty-one subjects (18 baclofen, 13 placebo) completed 72 hours of assessments, either entirely as inpatients or with outpatient follow-up. The need for high doses of benzodiazepines (20 mg or more of lorazepam over 72 hours) to control AWS was less likely in the baclofen treatment group (1 of 18) than in the placebo-treated group (7 of 13) (P = 0.004). We found that the use of baclofen was associated with a significant reduction in the use of high doses of benzodiazepine (lorazepam) in the management of symptomatic AWS. The use of low-dose baclofen in the management of AWS deserves further study, as reduced dependence on high-dose benzodiazepines in AWS management could improve patient safety.

A hemodialysis patient who developed neurotoxicity after taking a low dose of baclofen

A hemodialysis patient who developed neurotoxicity after taking a low dose of baclofen

Ethanol and Sucrose Seeking and Consumption Following Repeated Administration of the GABAB Agonist Baclofen in Rats

Baclofen, a GABA(B) agonist, has been found to decrease alcohol craving in humans and to nonselectively decrease ethanol intake in some rodent models. This experiment assessed the effects of repeated administration of baclofen on reinforcer seeking and consumption using the sipper tube appetitive/consummatory model of ethanol access. Subjects were divided into 2 groups and trained to make 30 lever press responses that resulted in access to either 10% ethanol or 2% sucrose in a sipper tube-drinking spout for 20 minutes. Three doses of baclofen were tested (0.3, 1.0, and 3.0 mg/kg) and each drug treatment was assessed using the following schedule: Monday, saline; Tuesday to Thursday, baclofen; and Friday, saline. The low dose of baclofen had no effect on the seeking or intake of either sucrose or ethanol, and the 1.0 mg/kg dose also had no effect on the appetitive, seeking response. However, the 1.0 mg/kg dose significantly decreased sucrose intake (from an average of 0.56 to 0.41 g/kg) and significantly increased ethanol intake (from an average of 0.77 to 1.00 g/kg). Similarly, the high dose (3.0 mg/kg) decreased sucrose intake and had a tendency to increase ethanol intake while decreasing both sucrose seeking and ethanol seeking. Overall, baclofen treatment affected reinforcer intake at doses that had no effect on reinforcer seeking, and effective doses decreased both sucrose seeking and ethanol seeking. Moreover, the effects on reinforcer intake were disparate, in that baclofen increased ethanol drinking and decreased sucrose drinking. The nonspecific effects of baclofen suggest that the GABA(B) system may be involved in general consummatory or drinking behaviors and does not appear to specifically regulate ethanol-motivated responding.

Effect of Low‐Dose Baclofen Administration on Plasma Insulin‐like Growth Factor‐I in Persons With Spinal Cord Injury

Patients with chronic spinal cord injury (SCI), a condition associated with reduced physical function, have been reported to have lower plasma insulin-like growth factor-I (IGF-I) levels than able-bodied persons. We evaluated the potential for daily low-dose baclofen administered over several weeks to increase plasma IGF-I levels. Ten healthy male outpatients with chronic SCI were studied prospectively. Patients received escalating doses of baclofen for 4 weeks at each dose level (5, 10, and 20 mg/d). At each dose of baclofen, an increase in the plasma IGF-I was noted; significant increases in plasma IGF-I occurred at 2 weeks after administration of drug at doses of 10 and 20 mg/d, with a subsequent rise to peak levels on baclofen 20 mg/d [baseline, 205+/-74; peak, 218+/-76 (not significant), 239+/-83 (P<.05), 263+/-87 microg/L (P<.05), at baclofen 5, 10, and 20 mg/d, respectively]. In conclusion, low-dose baclofen administration for 4 weeks stimulated the growth hormone-IGF-I axis in persons with SCI, with the potential for beneficial effects on body composition.

Baclofen neurotoxicity in chronic hemodialysis

Baclofen, a GABA agonist, is frequently used to treat muscle spasticity due to spinal cord injury and multiple sclerosis. Baclofen overdose can lead to coma, respiratory depression, hyporeflexia, and flaccidity. Because baclofen is primarily excreted unchanged through the kidneys, it should be given with caution, and it may be necessary to reduce the dosage.Signs of overdose may appear suddenly or insidiously. Acute massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of CNS depression, excessive salivation, dizziness, nausea and/or vomiting, somnolence, and hypotonia. Should overdose appear likely, the patient should be taken immediately to a hospital. A 46‐year‐old man, who was treated by intermittent hemodialysis (three times a week), was admitted to our unit for signs of CNS depression, dizziness, vomiting, somnolence, and hypotonia. He was treated at the relatively low dose of baclofen, 5 mg/day, because of muscle spasticity due to spinal cord injury. His temperature was 37 °C, and predialysis laboratory data were hemoglobin 11.4 g/dl, white blood cells 6550/mm3 with normal differential count, and platelets 330000/mm3. Serum sodium was 134 mmol/l, potassium 6.4 mmom/l, bicarbonate 18.3 mmol/l, urea 30 mmol/l, creatinine 998 μmol/l, glucose 5.16 mmol/l, and calcium level 2.4 mmol/l. Serum transaminases were normal. A brain computerized tomography (CT) scan showed no abnormalities. Baclofen‐associated encephalopathy was considered to be the most likely etiology for this acute neurological picture. Baclofen was then stopped. Plasma concentration of baclofen was &gt;600 ng/ml (therapeutic range 80–400 ng/ml) after 2 hours of hemodialysis and the baclofen level rapidly fell (&lt;200 ng/ml) at the end of the hemodialysis session. After the first 4‐h haemodialysis session, there was an incomplete recovery of the neurological status. After a renewed hemodialysis session the symptoms completely receded.The patient was discharged from the hospital 72 h later in a good condition. Patients with severely impaired renal function generally develop baclofen intoxication soon after the initiation of low‐dose therapy. Thus, the administration of baclofen, regardless of the dosage, in these patients is not appropriate.

THE EFFECT OF GABAB RECEPTOR ACTIVATION WITHIN THE VENTRAL TEGMENTAL AREA ON MORPHINE-INDUCED INCENTIVE SENSITIZATION IN FEMALE RATS

Repeated administration of morphine sensitizes animals to the stimulant and rewarding properties of the drug. It may also alter the expression and function of GABA receptors within the ventral tegmental area (VTA), a midbrain region that is implicated in morphine action. In the present study, the effect of activation of GABAB receptor subtypes within the VTA on morphine-induced incentive sensitization in female Wistar rats (250-300 g) was investigated. Female rats (n = 8) were chronically implanted with a 21-gauge cannula in the VTA (V = 8.5, L = 0.9, and A = -4.8 mm from bregma). One week after the surgery, the animals received morphine (5 mg/kg, s.c.) in their home cage for three consecutive days. Five days later, the animals were conditioned with an ineffective dose of morphine in a two compartment un-biased apparatus. Different doses of GABAB receptor agonist, baclofen (1.5, 6, and 12 ng/rat) were administered to the animals 5 min before the test. The results indicated that morphine administration to the animals in three consecutive days produces sensitization in which low doses of morphine (0.5 mg/kg, s.c.) induced CPP. Furthermore, administration of low doses of baclofen (1.5 and 6 ng/rat, i.VTA) enhanced, while higher doses of baclofen (12 ng/rat, i.VTA) reduced the morphine effects. The results indicated that activation of GABAB receptors within the VTA in morphine-sensitized animals produces a biphasic response, which may be due to pre and post GABAB receptor activation.

Dissociation of (−) Baclofen-Induced Effects on the Tail Withdrawal and Hindlimb Flexor Reflexes of Chronic Spinal Rats

We previously reported that the antinociceptive effect of the GABA B receptor agonist, (−)baclofen, in chronic spinal rats depended on the route of administration. That is, subcutaneous (SC) injections significantly increased the latency of the thermally elicited tail withdrawal (tail flick, TF) reflex, whereas spinal (intrathecal, IT) injections did not. The present studies attempted to determine the reason for this differential response. The possible contribution of a peripheral component to the systemic effect was evaluated, but was not supported by negative results of intradermal (−)baclofen injections (50 and 500 μg) into the tail skin of chronic spinal rats. A spinal site of action was indicated when pretreatment with 30 μg, IT of the GABA B receptor antagonist, phaclofen, significantly reduced the antinociceptive effect of SC (−)baclofen in both chronic spinal (5 mg/kg) and intact rats (2 mg/kg). Moreover, direct IT injections of (−)baclofen in chronic spinal rats produced a modest, but statistically significant increase in TF latency at doses of 0.06, 0.12, 0.3, and 0.6 μg, but not 1.2 μg. In the same spinal preparation, the flexor response was significantly reduced by IT injection of 0.6 and 1.2 μg, but not lower doses of 0.3 and 0.12 μg. These results provide the first quantitative, electrophysiological evidence of an antispastic effect of IT (−)baclofen in an in vivo, unanesthetized animal model. Second, the data show a separation between an antinociceptive effect of low spinal doses and an antispastic/muscle relaxant effect at higher doses, which may account for the results of our prior report. Finally, the data are also consistent with behavioral reports of antiallodynic/analgesic effects of low-dose baclofen, and may be relevant to the electrophysiological evidence of a preferential presynaptic action of low-dose (−)baclofen at the primary afferent synapse.

Contribution of C-fiber afferent nerves and autonomic pathways in the urinary bladder to spinal c-fos expression induced by bladder irritation

Previous studies have revealed that chemical irritation of the urinary bladder and urethral mucosa increases the expression of the immediate-early gene, c-fos, in the lumbosacral spinal cord of the rat. The present experiments were undertaken to determine whether drugs known to suppress bladder reflex pathways or spinal nociceptive mechanisms would influence c-fos expression induced by chemical irritation of the lower urinary tract (LUT). Capsaicin (100 mg/kg subcutaneous (sc), 7 days prior to the experiment) which does not block bladder reflexes but does desensitize C-fiber afferents, reduced (89%) the number of Fos-positive cells in the lumbosacral spinal cord induced by acetic acid-induced irritation of the LUT. Morphine (2.5 mg/kg, intravenous (iv)) or a low dose of baclofen, a GABAB agonist, both of which markedly suppressed reflex bladder activity, did not alter spinal c-fos expression induced by LUT irritation. However, a larger dose of baclofen (10 mg/kg, iv) reduced by 45% the number of Fos-positive cells. Clonidine (200 mug/kg, iv), an alpha2 adrenergic agonist, depressed bladder reflexes but produced only a small decrease (25%) in c-fos expression in lateral laminae V-VII of the cord. The ganglionic blocking agent, hexamethonium, which blocks autonomic but not afferent pathways to the LUT, decreased c-fos expression by 50%. The results indicate that certain drugs can differentially affect reflex bladder activity and c-fos expression and that analgesic drugs which suppress somatic nociceptive pathways do not necessarily affect the c-fos expression induced by visceral nociceptive input.

Comparison of the Antitussive Effects of Codeine and the GABA-Agonist Baclofen

γ-Aminobutyric acid (GABA) is an inhibitory transmitter of the central nervous system that also exists in peripheral tissues, including the lung. The GABA-agonist baclofen has been shown, in animal studies, to inhibit cough via a central mechanism. We have recently demonstrated the antitussive activity of a 14-day course of low-dose oral baclofen in normal subjects. In the present study, we evaluated a standard cough suppressant, codeine, and compared its antitussive effect with that of a single dose of baclofen. 10 healthy, adult volunteers who had previously participated in a study evaluating the antitussive effect of a 14-day course of baclofen, underwent capsaicin cough challenge on three occasions, 2 hours after the ingestion of codeine (30mg), baclofen (40mg) or placebo, which were dispensed in a randomised, double-blind manner. During each study, the concentration of capsaicin inducing 5 or more coughs (C5) was determined. Significant suppression of cough was achieved by codeine (p = 0.021). Although a single dose of baclofen demonstrated cough suppression in some individuals, its effect was not significant for the study group as a whole (p = 0.066). The change in cough threshold from baseline (Δlog C5) produced by single doses of codeine and baclofen were not significantly different (p = 0.434). In light of our previous study that demonstrated the significant antitussive effect of a 14-day course of low-dose baclofen, the inability of a single, large dose of baclofen to suppress cough in the current study suggests the need for multiple administrations to achieve the optimal inhibitory effect of this agent.