Comparative Efficacy of Adjuvant Nonopioid Analgesia in Adult Cardiac Surgical Patients: A Network Meta-Analysis.

OBJECTIVES: To compare the relative efficacy of adjuvant nonopioid analgesic regimens in adult cardiac surgical patients. DESIGN: This frequentist, random-effects network meta-analysis (NMA) was prospectively registered on PROSPERO (CRD42021282913) and conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA). The risk of bias (RoB) and confidence of evidence were assessed by RoB 2 and Confidence in Network Meta-Analysis, respectively. Relevant databases were searched from inception to October 9, 2021. SETTING: A total of 124 (N = 26,257) randomized controlled trials were included, of which 110 were analyzed. PARTICIPANTS: Trials enrolling adults (≥18 years of age) undergoing cardiac surgery that compared nonopioid analgesics against other nonopioid analgesics, placebo, or no additional treatment, as adjuvants to standard analgesic management, and reported at least 1 of the outcomes of interest. MEASUREMENT AND MAIN RESULTS: Outcomes of interest included resting postoperative pain scores at 24 hours. Compared with standard care and/or placebo, pain scores were reduced significantly by 10 different regimens, including acetaminophen (N = 176; mean difference [MD] -0.66 points, 95% CI -1.16 to -0.15 points; high confidence), magnesium (N = 323; -0.05 points, 95% CI -0.07 to -0.02 points; high confidence), gabapentin (N = 96; MD -0.40 points, 95% CI -0.71 to -0.09; moderate confidence), and clonidine (N = 64; MD v0.38 points, 95% CI -0.73 to v0.04 points; moderate confidence). Indomethacin, diclofenac, magnesium, and gabapentin significantly reduced 24-hour opioid consumption. Four regimens significantly decreased the intensive care unit length of stay. Hydrocortisone, dexmedetomidine, and clonidine significantly decreased the duration of mechanical ventilation. Magnesium decreased, while methylprednisolone significantly increased, the risk of myocardial infarction. CONCLUSIONS: Given the increasing emphasis on enhanced recovery after surgery(ERAS) protocols and the eventual goal of limiting opiate prescriptions postoperatively, the authors' data suggested far greater use of nonopioid adjuncts to minimize pain and enhance recovery following cardiac surgery.

A Comprehensive Review of the Use of Alpha 2 Agonists in Spinal Anesthetics.

BACKGROUND: Spinal Anesthesia was the first regional anesthetic technique to be performed. It was performed by Dr. August Bier, known for the Bier block, and his colleagues on August 16, 1898. Dr. Bier opted for, what he referred to at the time as "cocainization of the spinal cord" by introducing 15 mg of cocaine intrathecally prior to the operation. The surgery was largely uneventful and painless. The patient only experienced some vomiting and a headache postoperatively. Dr. Bier's use of neuraxial anesthesia aimed to directly inject local anesthetics in and around the central nervous system (CNS) for more direct control of pain and anesthesia. Local anesthetics were an important discovery in anesthesiology. However, since the advent of local anesthetics and spinal anesthesia as an alternative technique to general anesthesia, much has been learned about both the benefits and adverse effects of local anesthetics. It was quickly learned that use of local anesthetics would be limited by their potential for life-threatening toxic effects. For this reason, there was a push towards development of novel local anesthetics that had a larger therapeutic window with less likelihood of serious side effects. In addition to developing newer local anesthetics, the idea of adding adjuvants provided an opportunity to potentially limit the life-threatening events. These adjuvants would include medications such as epinephrine and alpha-2 agonists, such as clonidine and dexmedetomidine. Other adjuvants include opioids, glucocorticoids, and mineralocorticoids. OBJECTIVES: In this review, we will delve further into the indications, contraindications, uses, mechanisms, and future of spinal anesthesia and its adjuvants. STUDY DESIGN: A literature review of recent publications in the field of alpha 2 agonists used in spinal anesthetics was carried out from 2015 to present day. Consensus opinions were formulated in various areas. SETTING: This literature review was carried out at various medical universities throughout the nation and Europe. LIMITATIONS: As research has only just begun in this field data is limited at this time. CONCLUSIONS: The use of spinal anesthesia provides a reliable dermatome blockade to facilitate many different surgical procedures. The combination of local anesthetics with opioid medications within the subarachnoid space has been the standard of care. Adjuvant medications like alpha 2 agonists may play a significant role in prolonging spinal blockade as well as limiting cardiovascular complications such as hypotension and bradycardia. The use of alpha 2 agonists instead of opioid medications intrathecally decreases pruritus and delayed respiratory depression. Animal models have demonstrated the synergistic effects of utilizing alpha 2 agonists with opioids in the subarachnoid space. The addition of clonidine to fentanyl and local anesthetic demonstrated a shorter time to neural blockade, but no significant change in duration of the spinal. Interestingly alpha 2 agonists with local anesthetics showed increase block duration compared to opioid with local anesthetics. Further human trials need to be undertaken to analyze the effectiveness of alpha 2 agonists in the intrathecal space, but preliminary data does indicate it is an exemplary alternative to opioids.

Opioid treatment for opioid withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opioid withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, seizures and neurodevelopmental problems. OBJECTIVES: To assess the effectiveness and safety of using an opioid for treatment of NAS due to withdrawal from opioids in newborn infants. SEARCH METHODS: We ran an updated search on 17 September 2020 in CENTRAL via Cochrane Register of Studies Web and MEDLINE via Ovid. We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for eligible trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi- and cluster-RCTs which enrolled infants born to mothers with opioid dependence and who were experiencing NAS requiring treatment with an opioid. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility and risk of bias, and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 16 trials (1110 infants) with NAS secondary to maternal opioid use in pregnancy. Seven studies at low risk of bias were included in sensitivity analysis. Opioid versus no treatment / usual care: a single trial (80 infants) of morphine and supportive care versus supportive care alone reported no difference in treatment failure (risk ratio (RR) 1.29, 95% confidence interval (CI) 0.41 to 4.07; very low certainty evidence). No infant had a seizure. The trial did not report mortality, neurodevelopmental disability and adverse events. Morphine increased days hospitalisation (mean difference (MD) 15.00, 95% CI 8.86 to 21.14; very low certainty evidence) and treatment (MD 12.50, 95% CI 7.52 to 17.48; very low certainty evidence), but decreased days to regain birthweight (MD -2.80, 95% CI -5.33 to -0.27) and duration (minutes) of supportive care each day (MD -197.20, 95% CI -274.15 to -120.25). Morphine versus methadone: there was no difference in treatment failure (RR 1.59, 95% CI 0.95 to 2.67; 2 studies, 147 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study reported no difference in days hospitalisation (MD 1.40, 95% CI -3.08 to 5.88; 116 infants; low certainty evidence), whereas data from two studies found an increase in days treatment (MD 2.71, 95% CI 0.22 to 5.21; 147 infants; low certainty) for infants treated with morphine. A single study reported no difference in breastfeeding, adverse events, or out of home placement. Morphine versus sublingual buprenorphine: there was no difference in treatment failure (RR 0.79, 95% CI 0.36 to 1.74; 3 studies, 113 infants; very low certainty evidence). Neonatal or infant mortality and neurodevelopmental disability were not reported. There was moderate certainty evidence of an increase in days hospitalisation (MD 11.45, 95% CI 5.89 to 17.01; 3 studies, 113 infants), and days treatment (MD 12.79, 95% CI 7.57 to 18.00; 3 studies, 112 infants) for infants treated with morphine. A single adverse event (seizure) was reported in infants exposed to buprenorphine. Morphine versus diluted tincture of opium (DTO): a single study (33 infants) reported no difference in days hospitalisation, days treatment or weight gain (low certainty evidence). Opioid versus clonidine: a single study (31 infants) reported no infant with treatment failure in either group. This study did not report seizures, neonatal or infant mortality and neurodevelopmental disability. There was low certainty evidence for no difference in days hospitalisation or days treatment. This study did not report adverse events. Opioid versus diazepam: there was a reduction in treatment failure from use of an opioid (RR 0.43, 95% CI 0.23 to 0.80; 2 studies, 86 infants; low certainty evidence). Seizures, neonatal or infant mortality and neurodevelopmental disability were not reported. A single study of 34 infants comparing methadone versus diazepam reported no difference in days hospitalisation or days treatment (very low certainty evidence). Adverse events were not reported. Opioid versus phenobarbital: there was a reduction in treatment failure from use of an opioid (RR 0.51, 95% CI 0.35 to 0.74; 6 studies, 458 infants; moderate certainty evidence). Subgroup analysis found a reduction in treatment failure in trials titrating morphine to ≧ 0.5 mg/kg/day (RR 0.21, 95% CI 0.10 to 0.45; 3 studies, 230 infants), whereas a single study using morphine < 0.5 mg/kg/day reported no difference compared to use of phenobarbital (subgroup difference P = 0.05). Neonatal or infant mortality and neurodevelopmental disability were not reported. A single study (111 infants) of paregoric versus phenobarbital reported seven infants with seizures in the phenobarbital group, whereas no seizures were reported in two studies (170 infants) comparing morphine to phenobarbital. There was no difference in days hospitalisation or days treatment. A single study (96 infants) reported no adverse events in either group. Opioid versus chlorpromazine: there was a reduction in treatment failure from use of morphine versus chlorpromazine (RR 0.08, 95% CI 0.01 to 0.62; 1 study, 90 infants; moderate certainty evidence). No seizures were reported in either group. There was low certainty evidence for no difference in days treatment. This trial reported no adverse events in either group. None of the included studies reported time to control of NAS. Data for duration and severity of NAS were limited, and we were unable to use these data in quantitative synthesis. AUTHORS' CONCLUSIONS: Compared to supportive care alone, the addition of an opioid may increase duration of hospitalisation and treatment, but may reduce days to regain birthweight and the duration of supportive care each day. Use of an opioid may reduce treatment failure compared to phenobarbital, diazepam or chlorpromazine. Use of an opioid may have little or no effect on duration of hospitalisation or treatment compared to use of phenobarbital, diazepam or chlorpromazine. The type of opioid used may have little or no effect on the treatment failure rate. Use of buprenorphine probably reduces duration of hospitalisation and treatment compared to morphine, but there are no data for time to control NAS with buprenorphine, and insufficient evidence to determine safety. There is insufficient evidence to determine the effectiveness and safety of clonidine.

The Influence of Xylazine and Clonidine on Lung Ultrasound-Induced Pulmonary Capillary Hemorrhage in Spontaneously Hypertensive Rats.

Induction of pulmonary capillary hemorrhage (PCH) by lung ultrasound (LUS) depends not only on physical exposure parameters but also on physiologic conditions and drug treatment. We studied the influence of xylazine and clonidine on LUS-induced PCH in spontaneously hypertensive and normotensive rats using diagnostic B-mode ultrasound at 7.3 MHz. Using ketamine anesthesia, rats receiving saline, xylazine, or clonidine treatment were tested with different pulse peak rarefactional pressure amplitudes in 5 min exposures. Results with xylazine or clonidine in spontaneously hypertensive rats were not significantly different at the three exposure pulse peak rarefactional pressure amplitudes, and thresholds were lower (2.2 MPa) than with saline (2.6 MPa). Variations in LUS PCH were not correlated with mean systemic blood pressure. Similar to previous findings for dexmedetomidine, the clinical drug clonidine tended to increase susceptibility to LUS PCH.

Paroxysmal localized Hyperhidrosis, a case-report: When excessive sweating occurs in combination with severe headaches.

BACKGROUND: Paroxysmal localized hyperhidrosis is a rare disorder of the central autonomic nervous system. No association between paroxysmal hyperhidrosis and severe headache has been previously described in literature.Case description: A 65-year-old woman with idiopathic paroxysmal localized hyperhidrosis combined with severe holocranial headache attacks is described in this case report. Extensive diagnostic testing by means of laboratory examinations, 24-hour urinalyses, chest X-ray, abdominal ultrasound and computed tomography scans, and brain and spinal cord magnetic resonance imaging could not identify an underlying disorder. A diagnosis of idiopathic paroxysmal localized hyperhidrosis was made, and the patient was successfully treated with clonidine 0.075 mg three times a day, without any side effects. CONCLUSION: Paroxysmal localized hyperhidrosis is a rare central autonomic nervous system disorder that can occur in combination with severe headache. Both the headache and paroxysmal hyperhidrosis complaints were treated effectively with clonidine in the patient described in this case-report.

Effect of Apraclonidine and Diclofenac on Early Changes in Intraocular Pressure After Selective Laser Trabeculoplasty.

PRéCIS:: Adjuvant diclofenac and apraclonidine eye drop given in conjunction with selective laser trabeculoplasty (SLT) do not significantly impact medium-term intraocular pressure (IOP) reduction compared with placebo, but apraclonidine can be used to blunt immediate postlaser pressure spikes. PURPOSE: There is limited high-grade evidence guiding the choice of eye drops given before and after SLT. The authors chose to measure IOP during the first 24 hours, at 1 week, 6 weeks, and 6 months after SLT, and compare the effect of apraclonidine before SLT and diclofenac after SLT, with placebo. MATERIALS AND METHODS: In this double-blind, randomized, placebo-controlled trial, patients with open-angle glaucoma or ocular hypertension referred for SLT were recruited between 2016 and 2018. Patients were randomized to receive either apraclonidine pre-SLT with placebo post-SLT, placebo pre-SLT with diclofenac post-SLT, or placebo before and after SLT. RESULTS: Sixty eyes from 35 patients were treated with 360-degree SLT. Twenty-four-hour IOP measurements with patient self-monitoring after SLT demonstrated a moderate IOP spike at 1 hour and 2 hours post-SLT in the placebo and diclofenac study arms (mean=+4.05±0.58 mm Hg and +4.47±0.73, respectively, P<0.001 vs. pre-SLT IOP), which was prevented by apraclonidine (mean=-2.41±0.88 mm Hg, P<0.0001 vs. other study arms post-SLT). There were no significant differences between the 3 arms of the study on the long-term IOP reduction achieved by SLT (6 wk: P=0.51, 6 mo: P=0.42). CONCLUSIONS: Neither the use of apraclonidine before SLT nor diclofenac after SLT significantly influenced the IOP reduction induced by SLT. Except for a slight and transient reduction in intraocular inflammation, there was no beneficial effect of diclofenac on early IOP changes or the degree of patient discomfort relative to placebo.

Italian consensus on treatment of spasticity in multiple sclerosis.

BACKGROUND: Spasticity is a frequent multifactorial manifestation of multiple sclerosis (MS), affecting mostly the chronic courses of the disease. Its impact on patient functioning and quality of life is profound. Treatment of spasticity includes oral and intrathecal anti-spastic drugs, muscle injections with relaxant agents, physical therapy, electrical and magnetic stimulation and peripheral nerve stimulation, alone or in various combinations. METHODS: This Italian consensus on the treatment of spasticity in MS was produced by a large group of Italian MS experts in collaboration with neurophysiologists, experts in the production of guidelines and patients' representatives operating under the umbrella of the Italian Neurological Society, the Associazione Italiana Sclerosi Multipla and the European Charcot Foundation. This guideline was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 11 questions were formulated following the PICO framework (patients, intervention, comparator, outcome). Controlled studies only were included in the analysis. RESULTS: Despite some consistent limitations due to the poor methodological quality of most studies, there was a consensus on a strong recommendation for the use of intrathecal baclofen, oromucosal spray of nabiximols and intramuscular injection of botulinum toxin. The level of recommendation was weak for oral baclofen, tizanidine, gabapentin, benzodiazepines and transcranial magnetic stimulation. CONCLUSIONS: There is a clear need for new larger multicentre well-designed clinical trials with a duration that allows the persistence of the effects and the long-term safety of the interventions to be evaluated.

The role of Smyrnium cordifolium Boiss extract and curzerene on withdrawal syndrome in mice.

Morphine is the most effective medication to relieve pain, antinociception and withdrawal syndrome, but clinical application of these compounds is greatly affected by the occurrence of addiction. The aim of this research was the influence of SE and curzerene (Cur) on withdrawal syndrome signs in mice contrasted with clonidine. Extraction of the S. cordifolium extract (SE) was done by the Soxhlet method. Addiction was produced using the subcutaneous injections of morphine for 7 days. To estimate the influences of SE and Cur, the 64 male mice were separated into eight of 8. Sets 1, 2 and 3 were treated SE (100,200,300 mg/kg). Sets 4, 5 and 6 were treated Cur (0.03, 0.06, 0.12mg/kg). The findings showed that curzerene was the most important effective component S. cordifolium extract. Curzerene and SE reduced the mean of weight loss, diarrhea, and wet dog shakes in morphine-dependent mice in comparison with clonidine. All doses of Curzerene and SE extract reduced the locomotor activity and body weight loss when compared to the control group in morphine-dependent mice but not to clonidine compared. The SE (100mg/kg) and Cur (0.03mg/kg) are reduced signs of withdrawal syndrome equally to clonidine. SE (200 mg/kg) and Cur (0.06 mg/kg), are reduced of the body weight loss significantly in relation to clonidine (P<0.05). SE (200 mg/kg) and Cur (0.06 mg/kg), are reduced of diarrhea significantly in relation to clonidine (P<0.01). This was while SE (300mg/kg) and cur (0.12mg/kg) had deadly effect. Curzerene and SE are able to decrease the signs of withdrawal syndrome, which might have a human therapeutic capacity. Curzerene may be one of the terpenoids responsible for the effect of the S. cordifolium extract. Nevertheless, more investigations are needed to determine the exact mechanism of the effect of SE and curzerene.

[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.

Hypertensive Urgency: An Undesirable Complication of a "Male Performance" Herbal Product.

BACKGROUND: Hypertensive urgency is a clinical scenario that may be associated with herbal supplement use and that requires special consideration with regard to emergency department management. CASE REPORT: A 49-year-old man presented to the emergency department with palpitations and severely elevated blood pressure without evidence of end organ dysfunction. Hypertension failed to be controlled with multiple doses of oral clonidine and intravenous labetalol. The patient later admitted to using an herbal supplement containing yohimbine, a selective ⍺2-adrenoreceptor antagonist specifically linked to cases of refractory hypertension. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Between 17-35% of the U.S. adult population may use herbal supplements on a sporadic or regular basis; pharmacologically active agents in herbal supplements may affect both a patient's presentation and response to treatment. Most patients do not mention over-the-counter and herbal products in their medication profile unless specifically asked, and therefore it is important for emergency physicians to be aware of the pharmacologic effects of herbal supplements in the evaluation and treatment of refractory severe hypertension.

Antiasthmatic potential of Zizyphus jujuba Mill and Jujuboside B. - Possible role in the treatment of asthma.

Zizyphus jujuba Mill, a famous oriental traditional medicine, has been reported to exhibit diverse activities in biological systems including the respiratory system. However, a little information is available on its antiasthmatic activity. Jujuboside B (JB) is a natural saponin and one of the active constituent of fruits of Zizyphus jujuba. In the present investigation, JB was isolated from ethanolic extracts of fruits of Zizyphus jujuba (EZJF). EZJF and JB were then evaluated for anti-asthmatic activity using various screening methods. JB was additionally evaluated using ovalbumin (OVA) -induced allergic asthma in mice. Results obtained in the present study showed that EZJF and JB significantly inhibited clonidine-induced catalepsy, milk-induced leucocytosis and eosinophilia, clonidine-induced mast cell degranulation, and passive paw anaphylaxis. The number of inflammatory cells in bronchoalveolar lavage (BAL) fluid was considerably lowered and the severity of pulmonary inflammation was alleviated in the mice pretreated with JB. The high-level expression of T-helper type 2 (TH2) cytokines was markedly reduced in the serum, BAL fluid, and lung homogenates. Thus EZJF and JB showed potent anti-asthmatic activity. Hence EZJF and JB possess a potential role in the treatment of asthma.

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.

Neuropathic Pain Creates an Enduring Prefrontal Cortex Dysfunction Corrected by the Type II Diabetic Drug Metformin But Not by Gabapentin.

Chronic pain patients suffer from pain-related cognitive deficits, even when taking commonly prescribed analgesics. These deficits are likely related to pain-related maladaptive plasticity in the frontal cortex. We sought to model cognitive deficits in mice with neuropathic pain to examine maladaptive morphological plasticity in the mPFC and to assess the effects of several therapeutics. We used an attentional set-shifting task in mice with spared nerve injury (SNI) who received either a single intrathecal injection of an analgesic dose of clonidine, 7 d of 100 mg/kg gabapentin, or 7 d of 200 mg/kg metformin. Male SNI mice were significantly more impaired in the set-shifting task than females. This deficit correlated with a loss of parvalbumin (PV) and reductions in axon initial segment (AIS) length in layers 5/6 of the infralimbic (IL) cortex. Acute pain relief with clonidine had no effect on set-shifting performance, whereas pain relief via 7 day treatment with gabapentin worsened the impairment in both SNI and sham mice. Gabapentin reversed the PV loss in the IL but had no effect on AIS length. Treatment with the AMPK-activator metformin completely reversed the pain-related cognitive impairment and restored AIS length in the IL but had little effect on PV expression. Our findings reveal that neuropathic pain-related cognitive impairments in male mice are correlated to bilateral morphological changes in PV interneurons and layer 5/6 IL pyramidal neuron AIS. Pain relief with metformin can reverse some of the functional and anatomical changes.SIGNIFICANCE STATEMENT Cognitive impairments are a comorbidity of neuropathic pain but are inadequately addressed by existing therapeutics. We used a neuropathic pain model in mice to demonstrate that male (but not female) mice show a robust pain-related deficit in attentional set-shifting, which is associated with structural plasticity in axon initial segments in the infralimbic cortex. These deficits were completely reversed by 7 day treatment with the antidiabetic drug metformin, suggesting that this drug can be repurposed for the treatment of neuropathic pain and its cognitive comorbidities. Our findings have implications for our understanding of how neuropathic pain causes structural plasticity in the brain, and they point to a marked sexual dimorphism in neuropathic pain mechanisms in mice.

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.

Analysis of Drug-Drug Interactions in Swiss Claims Data Using Tizanidine and Ciprofloxacin as a Prototypical Contraindicated Combination.

BACKGROUND: Potential drug-drug interactions (pDDIs) are described in various case reports, but few studies have evaluated the impact of specific combinations on a population level. OBJECTIVE: To analyze the type and frequency of multiple contraindicated (X-pDDIs) and major interactions (D-pDDIs) and to subsequently assess the impact of the particular combination of tizanidine and ciprofloxacin on outpatient physician visits and hospitalizations. METHODS: Anonymized Swiss claims data from 524 797 patients in 2014-2015 were analyzed. First, frequencies of X- and D-pDDIs were calculated. Next, a retrospective cohort study was conducted among patients prescribed tizanidine and ciprofloxacin (exposed, n = 199) or tizanidine and other antibiotics (unexposed, n = 960). Hospitalizations and outpatient physician visits within 7, 14, and 30 days after initiation of antibiotic therapy were evaluated using multiple binary logistic regression and multiple linear regression. RESULTS: The relative frequencies of X- and D-pDDIs were 0.4% and 6.65%, respectively. In the cohort study, significant associations between exposure to tizanidine and ciprofloxacin and outpatient physician visits were identified for 14 and 30 days (odds ratio [OR] = 1.61 [95% CI = 1.17-2.24], P = 0.004, and OR = 1.59 [95% CI = 1.1-2.34], P = 0.016). A trend for increased risk of hospitalization was found for all evaluated time periods (OR = 1.68 [95% CI = 0.84-3.17], OR = 1.52 [95% CI = 0.63-3.33], and OR = 2.19 [95% CI = 0.88-5.02]). Conclusion and Relevance: The interaction between tizanidine and ciprofloxacin is not only relevant for individual patients, but also at the population level. Further investigation of the impact of other clinically relevant DDIs is necessary to improve patient safety and reduce avoidable health care utilization.

Transcutaneous Electrical Nerve Stimulation in Treatment of Occipital Neuralgia: A Case Report.

Occipital neuralgia is the third most common headache syndrome after migraine and tension type headaches. There is no well-established treatment regimen for a reliable cure. The current case presents a 39-year-old woman, diagnosed with occipital neuralgia of idiopathic cause. The condition was difficult to control by conservative or interventional approaches. The patient was started on conventional transcutaneous electrical nerve stimulation, 3 sessions per week. After the procedure, the patient achieved significant pain relief: 1-2/10 on the numeric rating scale, pain initially being 10/10. With maintenance therapy consisting of physical therapy, deep tissue massage, and muscle relaxants, 12 months after starting transcutaneous electrical nerve stimulation therapy, she is pain free.

Evaluation of the effects of occlusal splint, trigger point injection and arthrocentesis in the treatment of internal derangement patients with myofascial pain disorders.

PURPOSE: In temporomandibular disorders (TMDs), unless splints are effective, combined therapies are performed. The aim of this study is to show the effectiveness of the local anaesthethic injections (trigger point injections) to the masticatory muscles. MATERIALS AND METHODS: The study was composed of TMD patients and the predictor variables were therapy combinations including stabilization splint (SS) therapy, SS+trigger point injection therapy (TPI) and arthrocentesis. The primary outcome variables were pain and jaw movements. The follow-ups were done at 1st and 3rd months. 56 patients who were treated for TMD with only SS or combined therapies were included in the study. The effects of additional TPIs were compared to SS therapy alone. Also the effect of arthrocentesis was evaluated too. RESULTS: All groups revealed significant decreases in pain scores. Decreases in mouth openings were observed in some of the patients in the injection groups. CONCLUSION: The combined treatment method in which the injections were applied at shorter time intervals, was a more effective method for decreasing VAS scores in TMD patients in this study but further studies are required.

Neonatal Abstinence Syndrome: Advances in Diagnosis and Treatment.

IMPORTANCE: Neonatal abstinence syndrome, which occurs as a result of in utero opioid exposure, affects between 6.0 and 20 newborns per 1000 live US births. There is substantial variability in how neonatal abstinence syndrome is diagnosed and managed. OBJECTIVE: To summarize key studies examining the diagnosis and management (both pharmacologic and nonpharmacologic) of neonatal abstinence syndrome published during the past 10 years. EVIDENCE REVIEW: PubMed, Web of Science, and CINAHL were searched for articles published between July 1, 2007, and December 31, 2017. Abstracts were screened and included in the review if they pertained to neonatal abstinence syndrome diagnosis or management and were judged by the authors to be clinical trials, cohort studies, or case series. FINDINGS: A total of 53 articles were included in the review, including 9 randomized clinical trials, 35 cohort studies, 1 cross-sectional study, and 8 case series-representing a total of 11 905 unique opioid-exposed mother-infant dyads. Thirteen studies were identified that evaluated established or novel neonatal abstinence syndrome assessment methods, such as brief neonatal abstinence syndrome assessment scales or novel objective physiologic measures to predict withdrawal. None of the new techniques that measure infant physiologic parameters are routinely used in clinical practice. The most substantial number of studies of neonatal abstinence syndrome management pertain to nonpharmacologic care-specifically, interventions that promote breastfeeding or encourage parents to room-in with their newborns. Although these nonpharmacologic interventions appear to decrease the need for pharmacologic treatment and result in shorter hospitalizations, the interventions are heterogeneous and there are no high-quality clinical trials to support them. Regarding pharmacologic interventions, only 5 randomized clinical trials with prespecified sample size calculations (4 infant, 1 maternal treatment) have been published. Each of these trials was small (from 26 to 131 participants) and tested different therapies, limiting the extent to which results can be aggregated. There is insufficient evidence to support an association between any diagnostic or treatment approach and differential neurodevelopmental outcomes among infants with neonatal abstinence syndrome. CONCLUSIONS AND RELEVANCE: Evidence pertaining to the optimal diagnosis and treatment strategies for neonatal abstinence syndrome is based on small or low-quality studies that focus on intermediate outcomes, such as need for pharmacologic treatment or length of hospital stay. Clinical trials are needed to evaluate health and neurodevelopmental outcomes associated with objective diagnostic approaches as well as pharmacologic and nonpharmacologic treatment modalities.

A mixed treatment comparison on efficacy and safety of treatments for spasticity caused by multiple sclerosis: a systematic review and network meta-analysis.

OBJECTIVES: This study is aimed at providing a quantitative evaluation on different therapies of spasticity caused by multiple sclerosis. DATA SOURCES: PubMed and Embase database. REVIEW METHODS: We searched for randomized controlled trials that met the requirements. Percentages of improved patients' spasticity scale, mild adverse effect and severe adverse effect were extracted as outcomes. The forest plots accompanied with surface under the cumulative ranking curves were used to reveal the efficacy and safety of these therapies. RESULTS: In all, 23 randomized controlled trials with a total of 2720 patients were included in our study. Cannabinoids and botulinum toxin had shown a significantly better efficacy than placebo in the percentage of improved patients. Botulinum toxin also showed such significant difference compared with tizanidine and baclofen. No significant difference was found in spasticity scale. Cannabinoids, tizanidine and diazepam had significantly more mild adverse effect reports than placebo. Surface under the cumulative ranking curves suggested that cannabinoids, botulinum toxin and transcutaneous electric nerve stimulation were preferable therapies. CONCLUSIONS: We recommended botulinum toxin as the optimal intervention for multiple sclerosis-related spasticity. Cannabinoids and transcutaneous electric nerve stimulation could also be considered as multiple sclerosis-related spasticity treatments but their safety remained to be verified.