Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention.

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid.

Gamma-aminobutyric acid (Gaba) is a non-proteinogenic amino acid that is widely present in microorganisms, plants, and vertebrates. So far, Gaba is well known as a main inhibitory neurotransmitter in the central nervous system. Its physiological roles are related to the modulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of sleeplessness and depression. Besides, various pharmaceutical properties of Gaba on non-neuronal peripheral tissues and organs were also reported due to anti-hypertension, anti-diabetes, anti-cancer, antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection, and intestinal protection. Therefore, Gaba may be considered as potential alternative therapeutics for prevention and treatment of various diseases. Accordingly, this updated review was mainly focused to describe the pharmaceutical properties of Gaba as well as emphasize its important role regarding human health.

Decreasing postoperative narcotics in reconstructive pelvic surgery: a randomized controlled trial.

BACKGROUND: Postoperative pain control is crucial to any successful recovery plan. Many currently used medication regimens are narcotic-focused. OBJECTIVE: The objective of our study was to evaluate the efficacy of a multimodal pain regimen after pelvic reconstructive surgery. STUDY DESIGN: The primary outcome measure was narcotic use. Secondary outcomes included pain, nausea, and constipation. Patients were randomized to either usual care postoperative treatment or multimodal pain regimen. Usual care included no specific preoperative or intraoperative medications, and postoperative narcotics with ibuprofen. Multimodal pain regimen included preoperative and postoperative celecoxib, gabapentin, intraoperative and postoperative intravenous and oral acetaminophen and ibuprofen, and narcotics as needed. All narcotics were converted to milligram equivalents of oral morphine for standardization according to Centers for Disease Control and Prevention guidelines where conversion factors for oral hydrocodone = 1, oral oxycodone = 1.5, and oral hydromorphone = 4. Patients were given the validated Brief Pain Inventory survey preoperatively (baseline), at postoperative day 1, and 1 week postoperatively. At 1 week, bowel function and narcotics usage was assessed. RESULTS: Seventy patients were randomized to the usual care arm and 68 to the multimodal pain regimen arm. Patients in the multimodal pain regimen arm used significantly fewer intravenous narcotics in the operating room (90.7 ± 39.1 mg vs 104.6 ± 33.5 mg; P = .026) and while in the hospital (10.8 ± 15.1 mg vs 31.2 ± 29.6 mg; P < .001) and were more likely to use 0 oral narcotics after discharge to home (34.8% of patients vs 10.6%; P = .001). Of the patients who did use oral narcotics after discharge to home, there was no difference in amount used between groups (121.3 ± 103.7 mg in the multimodal pain regimen arm vs 153.0 ± 113.8 mg in the usual care arm; P = .139). Total narcotic usage (operating room + hospital + home) was significantly less in the multimodal pain regimen arm of the study (195.5 ± 147.2 mg vs 304.0 ± 162.1 mg; P < .001). There were no significant differences in pain scores between the 2 arms of the study on either postoperative time point. There were no significant differences in antiemetic use while in hospital, consistency of first bowel movement, length of stay, or number of telephone calls to nurses in first 3 weeks postoperatively. CONCLUSION: A multimodal pain regimen in pelvic reconstructive surgery was found to decrease postoperative opioid requirements, while providing equivalent pain control.

Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis.

To synthesize evidence from available randomized controlled trials (RCT) to compare the efficacies of dopaminergic drugs (pramipexole, ropinirole and rotigotine) and α-2-δ ligands (gabapentin enacarbil and pregabalin) for the treatment of restless legs syndrome (RLS). We searched PubMed for all eligible RCTs. Network meta-analysis using frequentist methodology with random effect models was performed for mean changes in scores on the International RLS Study Group Rating Scale (IRLS) and for responder rates on Clinical Global Impressions-Improvement (CGI-I); analyzed as odds ratio (OR). Network meta-analysis of mean changes in IRLS data from 35 studies with 7333 participants showed that all treatments, in specific gabapentin enacarbil, followed by pregabalin and rotigotine were superior to placebo [mean reduction in IRLS scores: -5.31 (-6.74 to -3.87), -5.20 (-6.91 to -3.49), 5.17 (3.73-6.61), respectively] but there were no significant differences between active treatments. Network meta-analysis of 5137 participants from 24 studies showed that gabapentin enacarbil and rotigotine were associated with the highest CGI-I response rates [ORs: 5.68; (95% CI, 4.14-7.21); and 4.68 (2.87-6.49), compared to placebo, respectively]. No significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropinirole. Based on IRLS scores and CGI-I response rates, while gabapentin enacarbil, pregabalin and rotigotine stand out as the most efficacious of all examined drugs, it is noteworthy that no significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropiniriole (for CGI-I response rates).

Advances in pharmacotherapies for movement disorders in children: current limitations and future progress.

PURPOSE OF REVIEW: In childhood, movement disorders are generated by a very large number of disorders of the nervous system, and the very different developmental ages at which these occur make studies of pharmacotherapy efficacy extremely difficult. In most clinical practices, medication used in management is by trial and error, and limited by lack of efficacy and/or adverse drug reactions leading to drug intolerance. Nevertheless, symptom reduction using polypharmacy must be balanced against any accompanying comorbidities such as poor attention and concentration, constipation, ileus, urinary retention, blurred vision sedation and respiratory depression. RECENT FINDINGS: A 'personalised medicine' approach may lead to specific management breakthroughs that are beneficial to a wider number of children. At present, neuromodulation with implantable devices offers greater proven efficacy for dystonia, myoclonus and dystonic-choreoathetosis, but enteral, intravenous and, more recently, transdermal medication strategies with clonidine patches and enteral gabapentin may provide important relief for both home management and critical care settings. SUMMARY: The current review brings the clinician up-to-date with the latest, albeit limited, thinking on the pharmacological management of movement disorders in children by focussing on goal-directed outcome measures to improve clinical decision-making in an evidence-light clinical setting.

Efficacy of Mirogabalin (DS-5565) on Patient-Reported Pain and Sleep Interference in Patients with Diabetic Neuropathic Pain: Secondary Outcomes of a Phase II Proof-of-Concept Study.

OBJECTIVE: To evaluate the effects of mirogabalin on patient-reported pain and sleep interference in diabetic peripheral neuropathic pain (DPNP). SUBJECTS: Adults (≥18 years) with type 1 or 2 diabetes, glycosylated hemoglobin of 10% or less at screening, and DPNP for six months or more were eligible for participation. METHODS: Subjects (N = 452) were randomly assigned (2:1:1:1:1:1:1) to receive placebo, dose-ranging mirogabalin (5, 10, 15, 20, 30 mg/day), or pregabalin (300 mg/day) for five weeks. Secondary efficacy end points studied here included patient global impression of change (PGIC), modified brief pain inventory (BPI), and average daily sleep interference score (ADSIS). Correlation plots were generated to examine the relationship between ADSIS and average daily pain score (ADPS). RESULTS: At week 5, significant reductions in ADSIS were observed in the mirogabalin 15, 20, and 30 mg/day groups, compared with placebo (P < 0.05). Baseline ADSIS and ADPS were strongly correlated (R2 = 0.4407), as were mean changes from baseline in ADSIS and ADPS at week 5 (R2 = 0.6694). The mirogabalin 30 mg/day group showed significant improvement compared with placebo in four of six BPI subscales at end point; the mirogabalin 15 mg/day group showed significant improvement in three of six BPI subscales (P < 0.05). At end of treatment, the percentage of subject with PGIC status of "much improved or better" was greater in all mirogabalin dose groups than in the placebo group (P < 0.05). A low incidence of treatment-related adverse events was reported for mirogabalin. CONCLUSIONS: Results support the effectiveness of mirogabalin in improving patient-reported pain and sleep interference in DPNP.

Effects of the Antiepileptic Drugs Phenytoin, Gabapentin, and Levetiracetam on Bone Strength, Bone Mass, and Bone Turnover in Rats.

Long-term treatment with antiepileptic drugs (AEDs) is accompanied by reduced bone mass that is associated with an increased risk of bone fractures. Although phenytoin has been reported to adversely influence bone metabolism, little is known pertaining to more recent AEDs. The aim of this study was to evaluate the effects of gabapentin or levetiracetam on bone strength, bone mass, and bone turnover in rats. Male Sprague-Dawley rats were orally administered phenytoin (20 mg/kg), gabapentin (30 or 150 mg/kg), or levetiracetam (50 or 200 mg/kg) daily for 12 weeks. Bone histomorphometric analysis of the tibia was performed and femoral bone strength was evaluated using a three-point bending method. Bone mineral density (BMD) of the femur and tibia was measured using quantitative computed tomography. Administration of phenytoin significantly decreased bone strength and BMD, which was associated with enhanced bone resorption. In contrast, treatment with gabapentin (150 mg/kg) significantly decreased bone volume and increased trabecular separation, as shown by bone histomorphometric analysis. Moreover, the bone formation parameters, osteoid volume and mineralizing surface, decreased after gabapentin treatment, whereas the bone resorption parameters, osteoclast surface and number, increased. Levetiracetam treatment did not affect bone strength, bone mass, and bone turnover. Our data suggested that gabapentin induced the rarefaction of cancellous bone, which was associated with decreased bone formation and enhanced bone resorption, and may affect bone strength and BMD after chronic exposure. To prevent the risk of bone fractures, patients prescribed a long-term administration of gabapentin should be regularly monitored for changes in bone mass.

The synergistic potential of various teas, herbs and therapeutic drugs in health improvement: a review.

Tea is one of the most widely consumed non-alcoholic beverages in the world next to water. It is classified as Camellia sinensis and non-Camellia sinensis (herbal teas). The common bioactive compounds found mainly in green teas are flavan-3-ols (catechins) (also called flavanols), proanthocyanidins (tannins) and flavonols. Black tea contains theaflavins and thearubigins and white tea contains l-theanine and gamma-aminobutyric acid (GABA), while herbal teas contain diverse polyphenols. Phytochemicals in tea exhibit antimicrobial, anti-diabetic and anti-cancer activities that are perceived to be helpful in managing chronic diseases linked to lifestyle. Many of these phytochemicals are reported to be biologically active when combined. Knowledge of the synergistic interactions of tea with other teas or herbs in terms of biological activities will be of benefit for therapeutic enhancement. There is evidence that various types of teas act synergistically in exhibiting health benefits to humans, improving consumer acceptance and economic value. Similar observations have been made when teas and herbs or medicinal drugs were combined. The aim of this review is to highlight potential beneficial synergies between combinations of different types of teas, tea and herbs, and tea and medicinal drugs. © 2017 Society of Chemical Industry.

Abuse potential of gabapentin in dentistry.

Gabapentin is an anticonvulsant drug widely prescribed for various ailments, including orofacial pain. It was once thought to have no potential for abuse; however, the last decade has seen a dramatic rise in the nonmedical use of gabapentin, particularly among opioid-dependent patients. Gabapentin is sedating and interacts with other sedating medications such as opioids, which can lead to impairment and accidents and may raise the risk of overdose. Dentists must be aware of the potential for abuse of gabapentin and weigh its benefits against its risks when prescribing the drug.

Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review.

CONTEXT: In patients with cancer, pain is one of the most feared and burdensome symptoms. Adjuvant analgesics are an important cornerstone on which treatment of pain in patients with cancer is based. OBJECTIVES: To update our guidelines for the treatment of pain in patients with cancer, we performed a systematic review on the use of adjuvant analgesics in pain in cancer. METHODS: A systematic search of the literature was performed searching for articles that studied the effect of (1) antidepressants, (2) anti-epileptics, (3) N-methyl-d-aspartate (NMDA) receptor antagonists, and (4) other adjuvant analgesics in patients with cancer pain and described their effects on pain intensity and/or side effects. RESULTS: Based on the keywords and after reading the full papers, we could include 12 papers on anticonvulsants, 10 papers on antidepressants, four on NMDA receptor antagonists, and 10 papers on other adjuvant analgesics. The methodological quality of the included papers was graded as low to very low. Overall, there was a low quality of evidence that gabapentin, pregabalin, amitriptyline, and venlafaxine were effective in reducing pain intensity in patients with cancer pain. There was insufficient evidence on the effectiveness of lamotrigine, levetiracetam, NMDA antagonists, cannabinoids, corticosteroids, and local anesthetics on reducing pain intensity in patients with cancer pain. CONCLUSION: The quality of currently available evidence on the effectiveness of adjuvant analgesics in the treatment of cancer pain is low. The treatment of pain associated with cancer should be tailored to the patient's personal preferences.

An update on the pharmacologic management and treatment of neuropathic pain.

Neuropathic pain results directly from a lesion or disease of the somatosensory nervous system and can be central or peripheral in origin. Epidemiologic research suggests that 7% to 10% of the general population suffers from neuropathic pain, although the prevalence may be underestimated. Patients with neuropathic pain may experience anxiety, depression, insomnia, disability, and reduced quality of life. Treatment remains suboptimal because traditional drugs provide only modest pain relief. This article reviews the causes of neuropathic pain, patient presentation, diagnosis, and management strategies.

The Effect of Preoperative Gabapentin on Postoperative Nausea and Vomiting: A Meta-Analysis.

BACKGROUND: Preoperative gabapentin has been shown to improve postoperative pain and limit reliance on opioid analgesia. On the basis of an alternative mechanism, our group investigated the ability of preoperative gabapentin to prevent postoperative nausea and vomiting (PONV). METHODS: We performed a meta-analysis of trials that reported outcomes on the effect of preoperative gabapentin on PONV end points in patients undergoing general anesthesia. In our primary analysis, we calculated the pooled antiemetic effects of preoperative gabapentin in studies with PONV as the primary end point. In our secondary analysis, we calculated the pooled effects in trials involving preoperative gabapentin that reported on the side effects, nausea and vomiting. RESULTS: Among the trials designed with PONV as a primary end point (8 trials; n = 838), preoperative gabapentin was associated with a significant reduction in PONV (risk ratio [RR] = 0.60; 99% confidence interval [CI], 0.50-0.72; P < 0.0001), nausea (RR = 0.34; 99% CI, 0.20-0.56; P < 0.0001), and vomiting (RR = 0.34; 99% CI, 0.19-0.61; P = 0.0002) at 24 hours. Among all included trials (44 trials; n = 3489) that reported on the side effects, nausea and vomiting, similar reductions were noted in PONV with preoperative gabapentin administration. Subgroup analysis of trials excluding repeat dosing, thiopental induction, and nitrous oxide maintenance and including high-risk surgery resulted in similar PONV efficacy. Preoperative gabapentin is also associated with significantly increased rates of postoperative sedation (RR = 1.22; 95% CI, 1.02-1.47; P = 0.03) compared with control. CONCLUSIONS: Preoperative gabapentin is associated with a significant reduction in PONV among studies designed to investigate this end point. Preoperative gabapentin should be considered not only as part of a multimodal approach to postoperative analgesia, but also for prevention of PONV.

Preventing chronic postoperative pain.

Chronic postoperative pain is common. Nerve injury and inflammation promote chronic pain, the risk of which is influenced by patient factors, including psychological characteristics. Interventional trials to prevent chronic postoperative pain have been underpowered with inadequate patient follow-up. Ketamine may reduce chronic postoperative pain, although the optimum treatment duration and dose for different operations have yet to be identified. The evidence for gabapentin and pregabalin is encouraging but weak; further work is needed before these drugs can be recommended for the prevention of chronic pain. Regional techniques reduce the rates of chronic pain after thoracotomy and breast cancer surgery. Nerve-sparing surgical techniques may be of benefit, although nerve injury is not necessary or sufficient for chronic pain to develop.

An Open Label Clinical Trial of a Peptide Treatment Serum and Supporting Regimen Designed to Improve the Appearance of Aging Facial Skin.

A 14-week single-center clinical usage study was conducted to test the efficacy of a peptide treatment serum and supporting skincare regimen in 29 women with mild to moderately photodamaged facial skin. The peptide treatment serum contained gamma-aminobutyric acid (GABA) and various peptides with neurotransmitter inhibiting and cell signaling properties. It was hypothesized that the peptide treatment serum would ameliorate eye and facial expression lines including crow's feet and forehead lines. The efficacy of the supporting skincare regimen was also evaluated. An expert investigator examined the subjects at rest and at maximum smile. Additionally, the subjects completed self-assessment questionnaires. At week 14, the expert investigator found a statistically significant improvement in facial lines, facial wrinkles, eye lines, and eye wrinkles at rest when compared to baseline results. The expert investigator also found statistically significant improvement at week 14 in facial lines, eye lines, and eye wrinkles when compared to baseline results at maximum smile. In addition, there was continued highly statistically significant improvement in smoothness, softness, firmness, radiance, luminosity, and overall appearance at rest when compared to baseline results at the 14-week time point. The test regimen was well perceived by the subjects for efficacy and product attributes. The products were well tolerated with no adverse events.

J Drugs Dermatol. 2016;15(9):1100-1106.

Comparison of the effects of gabapentin and pregabalin on wound healing in rats.

Gabapentinoids are effective adjunct drugs for reducing postoperative pain. However, the effects of gabapentinoids on wound healing have not been evaluated yet. In this study we evaluated their effects on wound healing. A total of 17 male Wistar-Albino rats, 250-350 g, were divided into three groups randomly: control group (n = 5, 2 ml saline), gabapentin group (n = 6, 20 mg/kg gabapentin) and pregabalin group (n = 6, 20 mg/kg pregabalin). Until day 13 inflammation scores were significantly lower (P < 0·05) and wound healing was significantly better in the control group when compared with gabapentin and pregabalin groups (P < 0·001). Inflammation scores were significantly lower in pregabalin group when compared with gabapentin group until day 13. But wound healing was significantly better in gabapentin group than in pregabalin group between days 13 and 21. In conclusion when gabapentin and pregabalin were compared, although pregabalin decreases inflammation scores, gabapentin has better results in wound healing.

Effect of GABA Extract of Black Sticky Rice with Giant Embryo on Alcohol-Related Indices After Acute Alcohol Intake in Social Drinkers.

BACKGROUND: This study was performed to evaluate the effect and safety of a high-gamma-aminobutyric acid-containing extract (GABA extract) of black sticky rice with giant embryo (BSRGE) on alcohol-related indices after acute alcohol intake in social drinkers. METHODS: Subjects were randomized to the GABA extract (G) group, GABA extract and alcohol drinking (GA) group, or placebo intake and alcohol drinking (PA) group in a double-blind design. All subjects were administered GABA extract (200 mg GABA) or placebo at 9 am on study days 2 and 3, respectively. Subjects in the GA and PA groups were administered an equivalent dose of alcohol that was diluted in a drinking beverage for a total amount of 240 ml at 11 am on day 3. Blood alcohol concentration (BAC) and the Biphasic Alcohol Effects Scale were measured just before alcohol drinking, and 6 times after alcohol drinking. RESULTS: The peak and area under the curve (AUC) of the total stimulation scale score after alcohol intake in females were significantly higher in the GA than in the PA group, whereas no significant difference was found between the 2 groups in males. The peak and AUC of the total score on the sedation scale after alcohol intake in males were significantly lower in the GA than in the PA group, whereas both were significantly higher in the GA than in the PA group of females. The AUC for BAC in males was significantly lower in the GA than in the PA group, whereas no significant difference was found in females. No adverse events were reported in any of the groups including the G group. CONCLUSIONS: Coadministration of a GABA extract to social drinkers while drinking alcohol is supposed to affect alcohol-related indices in terms of pharmacodynamics and pharmacokinetics and did not induce any adverse events.