Intracranial hemorrhage after a single dose of Yohimbine in a chronic user of clonidine.

INTRODUCTION: Yohimbine, an alpha-2 adrenoreceptor antagonist found in a variety of supplements, has been historically used to treat libido, erectile dysfunction, xerostomia, and as a weight loss enhancement. Yohimbine toxicity causes a sympathomimetic syndrome as demonstrated by the case below of a female who developed an intracranial hemorrhage (ICH) following an ingestion of yohimbine. CASE: This case follows a 39-year-old female who presented to the emergency department (ED) with complaints of nausea, emesis, and flushing following the ingestion of a female sexual enhancement supplement labeled to contain yohimbine (BioXgenic Nature's Desire) one hour prior. The patient took her prescribed 0.1 mg clonidine when the symptoms commenced. Upon arrival, the patient's blood pressure was 198/93. She developed neurological sequelae including a left-sided facial droop and weakness of her right extremities. A computed tomography scan demonstrated an acute basal ganglia hemorrhage with mild mass effect and mild subarachnoid hemorrhage. She was transferred to a regional referral hospital and discharged 16 days later to a rehabilitation center with persistent neurological sequelae. DISCUSSION: This patient exhibited sympathetic toxicity temporally associated with yohimbine ingestion. Our patient also had a variety of risk factors that increased the likelihood of a poor outcome with yohimbine. Chronic use of clonidine is known to down-regulate alpha-2 receptors. This leads to dependence of clonidine to maintain adrenergic homeostasis and could potentiate the effects of yohimbine. To compound effects, our patient was also taking bupropion and desvenlafaxine, which inhibit norepinephrine reuptake, likely worsening our patient's sympathomimetic response. Despite the temporal relationship of our patient's ICH and ingestion of yohimbine, a definitive relationship cannot be inferred due to our lack of confirmatory testing of yohimbine content and possibility of adulterants. The U.S. Food and Drug Administration (FDA) does not regulate the supplement market strictly, with multiple studies illustrating variation among ingredients of supplements despite stated quantities on the labels. CONCLUSION: Dietary supplements are not required by the FDA to undergo efficacy or safety testing, necessitating clear post-marketing communication regarding potential adverse events from various supplements. Users should be aware of yohimbine-containing products and the possible side effects of toxicity. It is crucial that physicians and patients be aware of possible drug-supplement interactions of yohimbine and the presentation of sympathomimetic syndromes.

Use of clonidine in the treatment of Irukandji syndrome: A 4-year retrospective cohort study on safety, efficacy and clinical utility.

OBJECTIVE: Irukandji syndrome (IS) is an extremely painful condition that causes a significant catecholamine surge and sympathetic autonomic response related to the envenomation from certain types of jellyfish. Current management involves intravenous fluids, magnesium sulphate and large doses of opioids for symptom control. Clonidine, a centrally acting alpha-2 agonist, is often used as an analgesic adjunct to reduce opioid requirements in acute pain. The present study explores the safety and efficacy of clonidine in reducing opioid requirements in IS. METHODS: All patients diagnosed with IS at Cairns Hospital between 1 March 2016 and 30 April 2020, and participants from the Magnesium in Irukandji Study Trial, were included in this retrospective study (n = 114). Cases were separated into two groups depending on whether or not they received clonidine, and subsequently analysed according to pre- and post-intervention opioid requirements, clonidine dose administered and adverse effects. RESULTS: Notably, 39 patients with IS received ≥1 mcg/kg clonidine and the remaining 75 did not. There was no difference in oral morphine equivalent daily dose (oMEDD) between groups before clonidine administration; however, there was a significant reduction in oMEDD required after patients received clonidine (26.1 mg; 95% CI 4.6-47.7) compared with those who did not (66.6 mg; 95% CI 56.9-86.1) (F = 8.722, df = 1 × 224, P = 0.003). One episode of hypotension occurred following the intervention. CONCLUSION: Patients with IS who received clonidine required significantly lower opioid requirements than those who did not receive clonidine. Clonidine was safe to administer and should be considered early when treating IS. The optimal clonidine dose remains unclear and requires prospective studies to validate our findings.

[HTA and non-hormonal menopause treatment]. / HTA et traitements non-hormonaux de la ménopause.

Serotonin reuptake inhibitors, clonidine, gabapentin and pregabalin have shown moderate efficacy in menopausal disorders. The effect of phytoestrogens is reported to be modest, but the side effects are not well known.

Non-Hormonal Replacement Therapy Regimens: Do they have an Effect on Cardiovascular Risk?

INTRODUCTION: Menopause is associated with adverse effects on quality of life of perimenopausal and post-menopausal women. It also has an impact on the development of cardiovascular disease (CVD). Hormonal treatments are the most effective medications for menopausal symptoms relief. Given the fact that hormonal treatments are contraindicated for many women, non-hormonal treatment, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), gabapentin, pregabalin, clonidine and phytoestrogens, constitute alternative treatments. Nevertheless, little is known about their effects on CVD risk. METHODS: PubMed, EMBASE and Cochrane Library were searched for the effects of non-hormonal treatment on CVD risk, blood pressure, heart rate, lipids and glucose concentrations, weight gain, cardiovascular events, stroke, mortality and morbidity. RESULTS: Phytoestrogens, pregabalin and gabapentin seem to have no adverse effects on the cardiovascular system. Phytoestrogens, in particular, seem to reduce CVD risk through many pathways. On the other hand, SSRIs and SNRIs, although effective in reducing menopausal vasomotor symptoms, should be cautiously administered to women with known CVD (e.g. with cardiac arrhythmias, atherosclerotic disease or stroke). As clonidine has been associated with cardiovascular adverse effects, it should be administered only in cases where blood pressure regulation is mandatory. CONCLUSION: Further research is needed to produce definite conclusions regarding the cardiovascular safety of non-hormonal medications for menopausal symptoms relief.

Pharmacological therapies for management of opium withdrawal.

BACKGROUND: Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence and milder withdrawal symptoms than heroin. The evidence on withdrawal management of heroin might therefore not be exactly applicable for opium. OBJECTIVES: To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal. SEARCH METHODS: We searched the following sources up to September 2017: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, regional and national databases (IMEMR, Iranmedex, and IranPsych), main electronic sources of ongoing trials, and reference lists of all relevant papers. In addition, we contacted known investigators to obtain missing data or incomplete trials. SELECTION CRITERIA: Controlled clinical trials and randomised controlled trials on pharmacological therapies, compared with no intervention, placebo, other pharmacologic treatments, different doses of the same drug, and psychosocial intervention, to manage acute withdrawal from opium in a maximum duration of 30 days. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 13 trials involving 1096 participants. No pooled analysis was possible. Studies were carried out in three countries, Iran, India, and Thailand, in outpatient and inpatient settings. The quality of the evidence was generally very low.When the mean of withdrawal symptoms was provided for several days, we mainly focused on day 3. The reason for this was that the highest severity of opium withdrawal is in the second to fourth day.Comparing different pharmacological treatments with each other, clonidine was twice as good as methadone for completion of treatment (risk ratio (RR) 2.01, 95% confidence interval (CI) 1.69 to 2.38; 361 participants, 1 study, low-quality evidence). All the other results showed no differences between the considered drugs: baclofen versus clonidine (RR 1.06, 95% CI 0.63 to 1.80; 66 participants, 1 study, very low-quality evidence); clonidine versus clonidine plus amantadine (RR 1.03, 95% CI 0.86 to 1.24; 69 participants, 1 study); clonidine versus buprenorphine in an inpatient setting (RR 1.04, 95% CI 0.90 to 1.20; 1 study, 35 participants, very low-quality evidence); methadone versus tramadol (RR 0.95, 95% CI 0.65 to 1.37; 1 study, 72 participants, very low-quality evidence); methadone versus methadone plus gabapentin (RR 1.17, 95% CI 0.96 to 1.43; 1 study, 40 participants, low-quality evidence), and tincture of opium versus methadone (1 study, 74 participants, low-quality evidence).Comparing different pharmacological treatments with each other, adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) -3.56, 95% CI -5.97 to -1.15; 1 study, 60 participants, very low-quality evidence). Comparing clonidine with buprenorphine in an inpatient setting, we found no difference in withdrawal symptoms rated by a physician (MD -1.40, 95% CI -2.93 to 0.13; 1 study, 34 participants, very low-quality evidence), and results in favour of buprenorpine when rated by participants (MD -11.80, 95% CI -15.56 to -8.04). Buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in an outpatient setting (RR 0.35, 95% CI 0.19 to 0.64; 1 study, 76 participants). We found no difference in the comparison of methadone versus tramadol (MD 0.04, 95% CI -2.68 to 2.76; 1 study, 72 participants) and in the comparison of methadone versus methadone plus gabapentin (MD -2.20, 95% CI -6.72 to 2.32; 1 study, 40 participants).Comparing clonidine versus buprenorphine in an outpatient setting, more adverse effects were reported in the clonidine group (1 study, 76 participants). Higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high-dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low-quality evidence). AUTHORS' CONCLUSIONS: Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low-quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.

Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Cannabis use disorder is associated with substantial morbidity and, after alcohol, is the most common drug bringing adolescents and adults into treatment. At present, there are no FDA-approved medications for cannabis use disorder. Combined pharmacologic interventions might be particularly useful in mitigating withdrawal symptoms and promoting abstinence. OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, and lofexidine, an alpha-2 agonist, in treating cannabis dependence. METHODS: One hundred fifty six cannabis-dependent adults were enrolled and following a 1-week placebo lead-in phase 122 were randomized in a double-blind, placebo-controlled, 11-week trial. Participants were randomized to receive dronabinol 20mg three times a day and lofexidine 0.6 mg three times a day or placebo. Medications were maintained until the end of week eight, were then tapered over two weeks and patients were monitored off medications during the last study week. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow-back method. RESULTS: There was no significant difference between treatment groups in the proportion of participants who achieved 3 weeks of abstinence during the maintenance phase of the trial (27.9% for the medication group and 29.5% for the placebo group), although both groups showed a reduction over time. CONCLUSIONS: Based on this treatment study, the combined intervention did not show promise as a treatment for cannabis use disorder.

[Clinical and physiological rationale for use of clonidine with articaine and adrenaline for local anesthesia in pediatric dentistry].

The study evaluated the effect of local anesthesia with articaine in different combinations with epinephrine and clonidine (articaine (4%) + epinephrine (1:200 000), articaine (4%) + clonidine (1:100 000), articaine (4%) + epinephrine (1:200 000) + clonidine (1:100 000), articaine (4%) + epinephrine (1:400 000) + clonidine (1:100 000)), on a number of physiological parameters in pediatric dental practice that characterize cardiovascular system, patient's degree of adaptation to a stressful situation and efficacy of analgesia. It is shown that in terms of impact on the cardiovascular system and stress adaptation indicators anesthesia including combination of epinephrine (1: 200 000) and clonidine (1: 100 000) in the anesthetic solution is the safest. Furthermore, this method ensures the most appropriate analgesic effect.

Non-surgical interventions for the management of chronic pelvic pain.

BACKGROUND: Chronic pelvic pain is a common and debilitating condition; its aetiology is multifactorial, involving social, psychological and biological factors. The management of chronic pelvic pain is challenging, as despite interventions involving surgery, many women remain in pain without a firm gynaecological diagnosis. OBJECTIVES: To assess the effectiveness and safety of non-surgical interventions for women with chronic pelvic pain. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Specialised Register. We also searched (from inception to 5 February 2014) AMED, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS. We handsearched sources such as citation lists, trial registers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) on non-surgical management of chronic pelvic pain were eligible for inclusion. We included studies of women with a diagnosis of pelvic congestion syndrome or adhesions but excluded those with pain known to be caused by endometriosis, primary dysmenorrhoea (period pain), active chronic pelvic inflammatory disease or irritable bowel syndrome. We considered studies of any non-surgical intervention, including lifestyle, physical, medical and psychological treatments. DATA COLLECTION AND ANALYSIS: Study selection, quality assessment and data extraction were performed independently by two review authors. Meta-analysis was performed using the Peto odds ratio (Peto OR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CIs). The primary outcome measure was pain relief, and secondary outcome measures were psychological outcomes, quality of life, requirement for analgesia and adverse effects. The quality of the evidence was assessed by using GRADE methods. MAIN RESULTS: Twenty-one RCTs were identified that involved non-surgical management of chronic pelvic pain: 13 trials were included in the review, and eight were excluded. The studies included a total of 750 women-406 women in the intervention groups and 344 in the control groups. Included studies had high attrition rates, and investigators often did not blind adequately or did not clearly describe randomisation procedures. Medical treatment versus placebo Progestogen (medroxyprogesterone acetate (MPA)) was more effective than placebo at the end of treatment in terms of the number of women achieving a greater than 50% reduction in visual analogue scale (VAS) pain score immediately after treatment (Peto OR 3.00, 95% CI 1.70 to 5.31, two studies, n = 204, I(2) = 22%, moderate-quality evidence). Evidence of benefit was maintained up to nine months after treatment (Peto OR 2.09, 95% CI 1.18 to 3.71, two studies, n = 204, I(2) = 0%, moderate-quality evidence). Women treated with progestogen reported more adverse effects (e.g. weight gain, bloatedness) than those given placebo (high-quality evidence). The estimated effect of lofexidine on pain outcomes when compared with placebo was compatible with benefit and harm (Peto OR 0.42, 95% CI 0.11 to 1.61, one study, 39 women, low-quality evidence). Women in the lofexidine group reported more adverse effects (including drowsiness and dry mouth) than women given placebo (moderate-quality evidence). Head-to-head comparisons of medical treatments Head-to-head comparisons showed that women taking goserelin had greater improvement in pelvic pain score (MD 3, 95% CI 2.08 to 3.92, one study, n = 47, moderate-quality evidence) at one year than those taking progestogen. Women taking gabapentin had a lower VAS pain score than those taking amytriptyline (MD -1.50, 95% CI -2.06 to -0.94, n = 40, low-quality evidence). Study authors reported that no statistically significant difference was observed in the rate of adverse effects among women taking gabapentin compared with women given amytriptyline. The study comparing goserelin versus progestogen did not report on adverse effects. Psychological treatment Women who underwent reassurance ultrasound scans and received counselling were more likely to report improved pain than those treated with a standard 'wait and see' policy (Peto OR 6.77, 95% CI 2.83 to 16.19, n = 90, low-quality evidence). Significantly more women who had writing therapy as a disclosure reported improvement in pain than those in the non-disclosure group (Peto OR 4.47, 95% CI 1.41 to 14.13, n = 48, very low-quality evidence). No difference between groups in pain outcomes was noted when other psychological therapies were compared with standard care or placebo (quality of evidence ranged from very low to low). Studies did not report on adverse effects. Complementary therapy Distension of painful pelvic structures was more effective for pain when compared with counselling (MD 35.8, 95% CI 23.08 to 48.52 on a zero to 100 scale, one study, n = 48, moderate-quality evidence). No difference in pain levels was observed when magnetic therapy was compared with use of a control magnet (very low-quality evidence). Studies did not report on adverse effects.The results of studies examining psychological and complementary therapies could not be combined to yield meaningful results. AUTHORS' CONCLUSIONS: Evidence of moderate quality supports progestogen as an option for chronic pelvic pain, with efficacy reported during treatment. In practice, this option may be most acceptable among women unconcerned about progestogenic adverse effects (e.g. weight gain, bloatedness-the most common adverse effects). Although some evidence suggests possible benefit of goserelin when compared with progestogen, gabapentin as compared with amytriptyline, ultrasound versus 'wait and see' and writing therapy versus non-disclosure, the quality of evidence is generally low, and evidence is drawn from single studies.Given the prevalence and healthcare costs associated with chronic pelvic pain in women, RCTs of other medical, lifestyle and psychological interventions are urgently required.

Pharmacological and non-pharmacological management of sleep disturbance in children: an Australian Paediatric Research Network survey.

BACKGROUND: Australian paediatricians use a wide variety of practices when managing sleep disturbances in children, including use of melatonin and behavioral strategies. However, practice patterns around the use of strategies, dosing, and how the patient populations managed, are unknown. Results could inform guidelines for the management of child sleep disturbances. OBJECTIVE: We aimed to document management practices by Australian general paediatricians for paediatric sleep disturbances through an online survey sent to members of the Australian Paediatric Research Network (APRN) who are recruited from the Royal Australasian College of Physicians. RESULTS: 181 (49%) of 373 eligible paediatricians responded, with 101 prescribing melatonin. The most commonly prescribed medications for poor sleep initiation were melatonin (89.1%), clonidine (48%) and antihistamines (29%). Melatonin doses ranged from 0.5mg to 12mg and duration of treatment was as long as 200weeks. Less than half of the paediatricians were aware of any potential melatonin side effects. Most paediatricians (82%) reported using behavioral strategies for sleep disturbances, most commonly anxiety relaxation techniques (75%) for poor sleep initiation and graduated extinction (i.e. "controlled crying", 52%) for disrupted overnight sleep. CONCLUSIONS: Australian paediatricians use both pharmacological and non-pharmacological treatments for paediatric sleep disturbances. Melatonin is the most commonly prescribed medication, but wide variation in its prescribing suggests a lack of knowledge of recommended dosages and effectiveness. Given the prevalence and variation in prescribing, there is an urgent need to develop clear guidance for paediatricians managing children with sleep disturbance.

Adjuvants to local anaesthesia in ophthalmic surgery.

This article reviews the use of adjuvants to local anaesthesia for ophthalmic regional anaesthesia. Hyaluronidase, bicarbonate, epinephrine, muscle relaxants, opiates and clonidine have all been described singly and in combination for use as an adjuvant to ophthalmic regional anaesthesia. The article focuses on the efficacy of the adjuvants with regard to improving akinesia, analgesia, speed of onset and reducing block failure. A description of the pharmacological action of each adjuvant is given followed by a review of randomised control trials, dosage and notable papers on the subject. There is no effective consensus between anaesthetists or surgeons on the use of adjuvants to local anaesthesia and it so is the purpose of this review to draw attention to the wealth of current data and allow an informed decision on the choices available.

What can be done about hot flushes after treatment for breast cancer?

Breast cancer survivors frequently experience severe hot flushes as a result of their treatment. This can adversely affect their quality of life, compliance with treatment and overall survival. To relieve vasomotor symptoms, a variety of drugs have been used including clonidine, gabapentin, selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors. Stellate ganglion block (SGB) has recently emerged as a new technique against hot flushes and preliminary studies report encouraging efficacy with minimal complications. Other approaches include various alternative treatments and, in a few cases, hormone replacement therapy (HRT). All randomized, controlled studies of drugs, hormone treatments and alternative therapies for vasomotor symptoms have been reviewed and efficacy and safety noted. Side-effects of current medical treatments frequently outweigh the benefits--leading many patients to discontinue the medications. Statistically significant differences between placebo and test agent may not translate into a meaningful subjective benefit. Desvenlafaxine looks promising as does SGB, despite its invasive nature. The favorable safety profile of SGB is confirmed through the long experience of SGB performed for other medical purposes. The majority of non-HRT treatments for hot flushes are little better than placebo but early results from randomized trials of desvenlafaxine and pilot studies of SGB suggest that it is worthwhile to test their efficacy specifically in breast cancer survivors.

Acupoint stimulation with diluted bee venom (apipuncture) potentiates the analgesic effect of intrathecal clonidine in the rodent formalin test and in a neuropathic pain model.

UNLABELLED: Although intrathecal (i.t.) administration of the alpha(2)-adrenoceptor agonist clonidine has a pronounced analgesic effect, the clinical use of clonidine is limited by its side effects. Previously, our laboratory has demonstrated that the subcutaneous injection of diluted bee venom (DBV) into an acupoint (termed apipuncture) produces significant analgesic effect in various pain animal models. The present study was designed to examine whether DBV injection into the Zusanli acupoint (ST-36) could enhance lower-dose clonidine-induced analgesic effects without the development of hypotension, bradycardia, or sedation. In the mouse formalin test, DBV injection produced a dramatic leftward shift in the dose-response curve for clonidine-induced analgesia. In a rat neuropathic pain model i.t. clonidine dose dependently suppressed chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia, and this clonidine-induced analgesic effect was significantly potentiated by apipuncture pretreatment. DBV apipuncture alone or in combination with a low dose of i.t. clonidine produced an analgesic effect similar to that of the high dose of clonidine, but without significant side effects. The analgesic effect produced by the combination of i.t. clonidine and apipuncture was completely blocked by pretreatment with an alpha(2)-adrenoceptor antagonist. These data show that DBV-apipuncture significantly enhances clonidine-induced analgesia and suggest that a combination of low dose clonidine with acupuncture therapy represents a novel strategy for pain management that could eliminates clonidine's side effects. PERSPECTIVE: This study demonstrated that intrathecal clonidine-induced analgesia is significantly enhanced when it is combined with chemical acupuncture treatment. The administration of low-dose clonidine in combination with acupuncture produced a potent analgesic effect without significant side effects and thus represents a potential novel strategy for the management of chronic pain.

A comparative clinical study of the effects of the traditional Chinese medicine Jinniu capsules and lofexidine on acute heroin withdrawal symptoms.

OBJECTIVE: Jinniu capsules, comprised of herbs and marine product extracts, are traditionally used in Chinese medicine. In this randomized multicenter clinical trial we evaluated the efficacy and safety of Jinniu capsules used to treat the symptoms of heroin withdrawal, as compared with lofexidine. METHODS: Two hundred and twelve patients with heroin dependence were randomly assigned to the Jinniu capsule or lofexidine treatment groups during a 10-day double-blind clinical trial. The severity of their opiate withdrawal symptoms was measured daily for 10 days. Anxiety was measured on days 0, 5, and 10. Safety assessment of the drugs included measurement of vital signs and side effects, as well as laboratory tests. RESULTS: Withdrawal symptom and anxiety scores decreased gradually over the treatment period, and no significant differences were found between two groups. No severe adverse events occurred during the treatment. CONCLUSION: Jinniu capsules may be an effective and safe agent in the management of opiate withdrawal.

Sedation during ophthalmic surgery.

Sedation is frequently used during ophthalmic regional anaesthesia. There is no 'ideal' drug for sedation or analgesia. Various drugs either alone or in combination have been used with different methods of administration. This review includes the roles of sedation, the pharmacology of drugs and the safety of sedation in patients undergoing ophthalmic surgery.

Tai-Kang-Ning, a Chinese herbal medicine formula, alleviates acute heroin withdrawal.

The efficacy and safety of Tai-Kang-Ning (TKN) capsule, a traditional Chinese medicine formula, for the treatment of acute heroin withdrawal syndrome were investigated by conducting a double-blind, double-dummy, positive-controlled, and randomized trial. Sixty-four patients with acute heroin withdrawal syndrome were recruited. These patients were treated with either TKN or lofexidine in a fixed schedule of doses for 10 days. The results indicate that both treatments significantly reduced withdrawal symptoms by day 3, but there was no significant difference overall between lofexidine and TKN in efficacy or safety. These results demonstrate that TKN is effective in the treatment of moderate-to-severe acute heroin withdrawal syndrome with mild adverse effects.

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse.

INTRODUCTION: Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence. OBJECTIVES: The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an alpha(2)-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence. MATERIALS AND METHODS: Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured. RESULTS: THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone. CONCLUSIONS: These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.

Alcohol withdrawal syndrome: how to predict, prevent, diagnose and treat it.

(1) When people who are physically dependent on alcohol stop drinking, they experience an alcohol withdrawal syndrome. The symptoms generally resolve spontaneously within a week, but more severe forms may be associated with generalised seizures, hallucinations and delirium tremens, which can be fatal. (2) We carried out a literature review in order to obtain answers to the following questions: how to predict or rapidly diagnose a severe alcohol withdrawal syndrome; how to prevent and treat this syndrome; how to manage severe forms; and how to deal with the risk of vitamin B1 deficiency. (3) The main risk factors for severe withdrawal syndrome are: chronic heavy drinking; a history of generalised seizures; and a history of delirium tremens. (4) Anxiety, agitation, tremor, excessive sweating, altered consciousness and hallucinations are signs of a severe withdrawal syndrome. (5) Individual support and effective communication seem to reduce the risk of severe withdrawal syndrome. (6) Oral benzodiazepines are the best-assessed drugs for preventing a severe alcohol withdrawal syndrome, particularly the risk of seizures. When given for a maximum of 7 days, the adverse effects are usually mild. (7) Clinical trials of other antiepileptics suggest they are less effective than benzodiazepines, and their addition to benzodiazepine therapy offers no tangible advantage. (8) Betablockers increase the risk of hallucinations, and clonidine increases the risk of nightmares, and the efficacy of these two drugs is not well documented. Neuroleptics increase the risk of seizures. There are no convincing data to support the use of magnesium sulphate or meprobamate (the latter carries a risk of serious adverse effects). Acamprosate, naltrexone and disulfiram are not beneficial in alcohol withdrawal. (9) Gradual withdrawal, i.e. ingestion of decreasing amounts of alcohol, has not been compared with other methods but is generally not recommended. (10) There are no specific recommendations on hydration. Note that excessive water-sodium intake carries a risk of pulmonary oedema in patients with heart disease. (11) As vitamin B1 deficiency is frequent and can lead to serious complications in alcohol-dependent patients, oral vitamin B1 supplementation is widely recommended, despite the absence of comparative trials. High doses must be used to compensate for poor absorption. Intravenous administration is best if patients have very poor nutritional status or severe complications such as Gayet-Wernicke encephalopathy (a medical emergency), even though rare anaphylactic reactions have been reported after vitamin B1 injection. (12) Planned alcohol withdrawal in specialised hospital units has been extensively studied. Outpatient withdrawal may be more appropriate for patients who are at low risk of developing severe withdrawal syndrome. (13) A large proportion of alcohol-dependent patients were excluded from trials of withdrawal strategies. These include elderly patients, patients with serious psychiatric or somatic disorders, and patients who are also dependent on other substances. (14) An oral benzodiazepine is the best-assessed treatment for a single episode of generalised seizures or hallucinations during alcohol withdrawal. (15) In randomised comparative trials benzodiazepines were more effective than neuroleptics in preventing delirium-related mortality. Currently, with appropriate fluid-electrolyte support, continuous monitoring of vital signs, and respiratory support if necessary, the mortality rate for delirium tremens is under 3%. (16) In practice, patients who are attempting to stop drinking alcohol need close personal support and communication, and a reassuring environment, as well as regular monitoring for early signs of a withdrawal syndrome; the latter may require benzodiazepine therapy.

Effects of fasting on evaluation of gastrointestinal transit with charcoal meal.

INTRODUCTION: At the present time, most studies investigating gastrointestinal transit time with charcoal are conducted in fasted rats. It seems reasonable to hypothesize that the fasting state of rats could influence the effect a compound had on gastrointestinal transit time. The purpose of this study was to investigate the effects of food on the pharmacological effects on gastrointestinal transit. METHODS: For each drug investigated, two sets of 32 male Sprague-Dawley rats were used. One set was studied after being fasted for approximately 6 h, the second set was studied after free access to food. Each set had 4 groups of animals (n=8/group) that were administered different doses, allowing the assessment of the drug effect after fasting and after free access to food. Animals were administered 0, 10, 25, and 75 mg/kg of morphine; 0, 10, 20, and 40 mg/kg loperamide, or 0, 0.05, 0.5, and 3.0 mg/kg clonidine. At predetermined times, an activated charcoal suspension was administered by oral gavage. Thirty minutes after receiving the charcoal meal, rats were euthanized and the small intestine was removed. The length of the small intestine and the distance traveled by the charcoal were recorded. For each animal, gastrointestinal transit was calculated as the percentage of the distance traveled relative to the total length of the small intestine. RESULTS: Baseline (vehicle dosed animals) gastrointestinal transit was significantly greater in fasted versus fed rats. In fasted rats, morphine did not have a significant effect on transit. In fed rats, 25 and 75 mg/kg morphine caused a significant decrease in transit. In fed and fasted rats, 0.5 and 3 mg/kg clonidine caused a significant decrease in transit. Loperamide did not affect gastrointestinal transit in fed or fasted rats at doses up to 40 mg/kg. DISCUSSION: These data demonstrate that food does not reduce the sensitivity of the gastrointestinal transit time.

Reduction of adrenergic neurotransmission with clonidine aggravates spike-wave seizures and alters activity in the cortex and the thalamus in WAG/Rij rats.

The alpha-2 adrenoreceptor agonist clonidine in low dose inhibits the release of noradrenaline and aggravates absence seizures. The present study examines properties of two types of spike-wave discharges (SWD) in a genetic model of absence epilepsy, the WAG/Rij rats. After reduction of noradrenergic neurotransmission with clonidine (0.00625 mg/kg, i.p.), the electrical activity was recorded in the neocortex, the ventroposteromedial nucleus (VPM) and the reticular thalamic nucleus (RTN). Clonidine temporally reduced percentage of wakefulness but did not affect sleep. Clonidine decreased the spectral power of sleep EEG (mostly in the delta band), this effect was found in the cortex and in the VPM. Clonidine increased the incidence of SWD type I (generalized); the spectral power of SWD I was lower in the frontal cortex (mostly in 1-9 and 30-100 Hz) and in the VPM (1-5 Hz), but higher in the RTN (9-14 Hz). Local occipital SWD (type II) had a tendency to be less numerous after clonidine, they had a lower power in the 5-9 Hz band in the occipital cortex, in the VPM and in the RTN. It can be concluded that strengthening of 9-14 Hz activity in the RTN may underlie clonidine-induced aggravation of SWD I.

Differential effects of clonidine, dopamine, dobutamine, and dopexamine on basal and acid-stimulated mucosal blood flow in the rat stomach.

OBJECTIVE: To analyze the effects of clonidine, dopamine, dobutamine, and dopexamine on gastric mucosal blood flow (GMBF) at baseline and after stimulation by acid back diffusion through a disrupted gastric mucosal barrier. DESIGN: Prospective, randomized, unblinded study. SETTING: University research laboratory. SUBJECTS: Adult Sprague-Dawley rats. INTERVENTIONS: Mean arterial blood pressure (MAP) and heart rate (HR) were recorded from a carotid artery of the phenobarbital-anesthetized animals. A jugular vein was cannulated for continuous infusion of saline and intravenous drug administration. The stomach was prepared for luminal perfusion and for recording GMBF with the hydrogen gas clearance technique. Gastric mucosal vascular conductance (GMVC) was calculated as GMBF divided by MAP. MEASUREMENTS AND MAIN RESULTS: Clonidine (37.5 and 112.5 nmol x kg(-1)) lowered MAP and HR and caused gastric vasodilation as shown by a rise of GMVC. The 2.5-fold increase in GMVC elicited by gastric perfusion with HCl (0.15 M) plus ethanol (25%) was depressed by clonidine. All cardiovascular effects of clonidine were prevented by the alpha2-adrenoceptor antagonist idazoxan (2 micromol x kg(-1)). Infusion of dopamine (15 and 45 micromol x kg(-1) x hr(-1)), dobutamine, or dopexamine (each at 5 and 15 micromol x kg(-1) x hr(-1)) caused tachycardia. GMVC at baseline was attenuated by the higher dose of dopamine and dopexamine, but not dobutamine. In contrast, the acid-induced vasodilation in the gastric mucosa was depressed by dobutamine and dopexamine, but not dopamine. CONCLUSIONS: Clonidine, dobutamine, and dopexamine at high dosage suppress the gastric mucosal vasodilator response to acid back diffusion, which is an important defense mechanism. Although the dose equivalence between rats and humans is not known, the antivasodilator effects highlight an adverse action whereby large doses of dobutamine, dopexamine, and clonidine may compromise gastric mucosal homeostasis and facilitate stress ulcer formation. Dopamine lacks this detrimental activity.