Results from a randomized, double-blind, placebo-controlled, crossover, multimodal-MRI pilot study of gabapentin for co-occurring bipolar and cannabis use disorders.

Disrupted brain gamma-aminobutyric acid (GABA)/glutamate homeostasis is a promising target for pharmacological intervention in co-occurring bipolar disorder (BD) and cannabis use disorder (CUD). Gabapentin is a safe and well-tolerated medication, FDA-approved to treat other neurological diseases, that restores GABA/glutamate homeostasis, with treatment studies supporting efficacy in treating CUD, as well as anxiety and sleep disorders that are common to both BD and CUD. The present manuscript represents the primary report of a randomized, double-blind, placebo-controlled, crossover (1-week/condition), multimodal-MRI (proton-MR spectroscopy, functional MRI) pilot study of gabapentin (1200 mg/day) in BD + CUD (n = 22). Primary analyses revealed that (1) gabapentin was well tolerated and adherence and retention were high, (2) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels and (3) gabapentin increased activation to visual cannabis cues in the posterior midcingulate cortex (pMCC, a region involved in response inhibition to rewarding stimuli). Exploratory evaluation of clinical outcomes further found that in participants taking gabapentin versus placebo, (1) elevations of dACC GABA levels were associated with lower manic/mixed and depressive symptoms and (2) elevations of rBG glutamate levels and pMCC activation to cannabis cues were associated with lower cannabis use. Though promising, the findings from this study should be interpreted with caution due to observed randomization order effects on dACC glutamate levels and identification of statistical moderators that differed by randomization order (i.e. cigarette-smoking status on rBG glutamate levels and pMCC cue activation). Nonetheless, they provide the necessary foundation for a more robustly designed (urn-randomized, parallel-group) future study of adjuvant gabapentin for BD + CUD.

Anti-nociceptive effects of ECa 233 a standardized extract of Centella asiatica (L.) Urban on chronic neuropathic orofacial pain in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: ECa 233 is a standardized extract of Centella asiatica (L.) Urban, a herb traditionally used to treat a number of diseases including neurological disorders. Accordingly, ECa 233 showed benefits on animal models of cognitive deficits, chronic stress and Parkinson's disease. Analgesic activity of ECa 233 was shown in Tail's flick test in rodent and relieving aphthous ulcer pain in man. Moreover, acute and sub-chronic toxicity testing in rodents and pharmacokinetic study in healthy volunteers, clinical trial phase I demonstrated good safety profiles of ECa 233. AIM OF THE STUDY: This study aims to evaluate the anti-nociceptive effects of ECa 233 and its synergistic effect with gabapentin on chronic neuropathic orofacial pain after 3 weeks infraorbital nerve chronic constriction injury in mice. The peripheral and central nociceptive activities are also examined. MATERIALS AND METHODS: Chronic neuropathic orofacial pain was induced by 3 weeks infraorbital nerve chronic constriction injury. Mice were treated with ECa 233 (30, 100 and 300 mg/kg) and gabapentin (10 mg/kg) by oral gavage starting on day 21 and going on for 14 consecutive days. Mechanical hyperalgesia and allodynia were measured on day 7, 14, 21, 28 and 35 after infraorbital nerve chronic constriction injury. At the end of the experiment, mice were observed for the sedative effect using the locomotor activity, the calcitonin gen-related peptide in trigeminal ganglion and c-fos expression in trigeminal nucleus caudalis were investigated after euthanasia. RESULTS: Infraorbital nerve chronic constriction injury gradually induced marked ipsilateral mechanical hyperalgesia and allodynia. The maximum hyperalgesia and allodynia response presented on day 21 and the response was remained constant until day 35. Treatment with either 300 mg/kg ECa 233 or 10 mg/kg gabapentin were able to attenuate mechanical hyperalgesia and allodynia. The downregulation of calcitonin gen-related peptide on ipsilateral trigeminal ganglion were observed in ECa 233 at 100 and 300 mg/kg and 10 mg/kg gabapentin-treated groups. The c-fos expression on ipsilateral trigeminal nucleus caudalis was also decreased in 300 mg/kg ECa 233 and 10 mg/kg gabapentin-treated groups. CONCLUSION: ECa 233 reduced hyperalgesia and allodynia by modulating the peripheral calcitonin gen-related peptide expression consequently alleviate the nociceptive activity in trigeminal nucleus caudalis. Further clinical trial to proof ECa 233's efficacy in neuropathic pain in man as well as possible attributable mechanism of action should be further investigated.

Comparison between acupuncture therapy and gabapentin for chronic pain: a pilot study.

BACKGROUND: We examined whether the effect of true electroacupuncture on pain and functionality in chronic pain participants can be differentiated from that of medication (gabapentin) by analyzing quantitative sensory testing (QST). METHODS: We recruited chronic back and neck pain participants who received six sessions (twice weekly) of true electroacupuncture versus sham electroacupuncture or 3 weeks of gabapentin versus placebo treatment. QST profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after three sessions (visit 4) or six sessions (visit 7) of acupuncture or 3 weeks of gabapentin or placebo. RESULTS: A total of 50 participants were analyzed. We found no differences in QST profile changes (p = 0.892), pain reduction (p = 0.222), or functionality (p = 0.254) between the four groups. A major limitation of this pilot study was the limited number of study participants in each group. CONCLUSION: This pilot study suggests that a large-scale clinical study with an adequate sample size would be warranted to compare acupuncture and medication therapy for chronic pain management. TRIAL REGISTRATION NUMBER: NCT01678586 (ClinicalTrials.gov).

Day-of-Surgery Gabapentinoids and Prolonged Opioid Use: A Retrospective Cohort Study of Medicare Patients Using Electronic Health Records.

BACKGROUND: While preoperative gabapentinoids are commonly used in surgical multimodal analgesia protocols, little is known regarding the effects this therapy has on prolonged postsurgical opioid use. In this observational study, we used data from a large integrated health care system to estimate the association between preoperative day-of-surgery gabapentinoids and the risk of prolonged postsurgical opioid use. METHODS: We identified adults age ≥65 years undergoing major therapeutic surgical procedures from a large integrated health care system from 2016 to 2019. Exposure to preoperative gabapentinoids on the day of surgery was measured using inpatient medication administration records, and the outcome of prolonged opioid use was measured using outpatient medication orders. We used stabilized inverse probability of treatment-weighted log-binomial regression to estimate risk ratios and 95% confidence intervals (CIs) of prolonged opioid use, comparing patients who received preoperative gabapentinoids to those who did not and adjusting for relevant clinical factors. The main analysis was conducted in the overall surgical population, and a secondary analysis was conducted among procedures where at least 30% of all patients received a preoperative gabapentinoid. RESULTS: Overall, 13,958 surgical patients met inclusion criteria, of whom 21.0% received preoperative gabapentinoids. The observed 90-day risk of prolonged opioid use following surgery was 0.91% (95% CI, 0.77-1.08). Preoperative gabapentinoid administration was not associated with a reduced risk of prolonged opioid use in the main analysis conducted in a broad surgical population (adjusted risk ratio [adjRR], 1.19 [95% CI, 0.67-2.12]) or in the secondary analysis conducted in patients undergoing colorectal resection, hip arthroplasty, knee arthroplasty, or hysterectomy (adjRR, 1.01 [95% CI, 0.30-3.33]). CONCLUSIONS: In a large integrated health system, we did not find evidence that preoperative gabapentinoids were associated with reduced risk of prolonged opioid use in patients undergoing a broad range of surgeries.

Effect of preoperative gabapentin after transurethral prostate resection under general anesthesia. A randomized double-blind, placebo-controlled trial.

OBJECTIVES: To investigate whether preoperative oral gabapentin could reduce postoperative pain, analgesic consumption and the occurrence of catheter-related bladder discomfort (CRBD). Methods: In this study, participants randomly received either 600 mg gabapentin or placebo orally 2 h prior to transurethral prostate resection. Visual analogue scale and Ramsay sedation scale was utilized to assess pain intensity and sedation status after surgery. Intravenous 1.5 mg.kg-1 tramadol was used for postoperative analgesia. Pain intensity, sedation status, CRBD, tramadol consumption, side effects and the overall satisfaction degree were assessed and recorded for 48 h after tracheal extubation.  Results: Ninety participants given gabapentin and 91 participants given placebo completed the study. Lower visual analogue scale scores, less tramadol consumption, longer time to the first analgesic requirement, lower incidence of CRBD and nausea and higher satisfaction degree were detected in the patients receiving gabapentin compared with the patients receiving placebo.  Conclusion: Preoperative oral gabapentin reduced postoperative visual analogue scale scores, tramadol consumption and the occurrence rate of CRBD and nausea, and consequently, increased the degree of patients' satisfaction after transurethral prostate resection.

Increased Antiseizure Effectiveness with Tiagabine Combined with Sodium Channel Antagonists in Mice Exposed to Hyperbaric Oxygen.

Hyperbaric oxygen (HBO2) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO2 when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO2-induced seizures. A series of experiments in C57BL/6 mice exposed to 100% oxygen at 5 atmospheres absolute (ATA) were performed. We predicted equally effective doses from individual drug-dose response curves, and the combinations of tiagabine + carbamazepine or lamotrigine were tested to determine the maximally effective combined doses to be used in subsequent experiments designed to identify the type of pharmacodynamic interaction for three fixed-ratio combinations (1:3, 1:1, and 3:1) using isobolographic analysis. For both combinations, the maximally effective combined doses increased seizure latency over controls > 5-fold and were determined to interact synergistically for fixed ratios 1:1 and 3:1, additive for 1:3. These results led us to explore whether the benefits of these drug combinations could be extended to the lungs, since a centrally mediated mechanism is believed to mediate hyperoxic-induced cardiogenic lung injury. Indeed, both combinations attenuated bronchoalveolar lavage protein content by ~ 50%. Combining tiagabine with carbamazepine or lamotrigine not only affords greater antiseizure protection in HBO2 but also allows for lower doses to be used, minimizing side effects, and attenuating acute lung injury.

Effect of melatonin on the daytime sleepiness side-effect of gabapentin in adults patients with neuropathic pain / Efeito da melatonina sobre o efeito colateral de sonolência diurna da gabapentina em pacientes adultos com dor neuropática

Abstract Background and objectives: Gabapentin is an antiepileptic drug. Widely used for the management of neuropathic pain. Although it is known to be well tolerated, somnolence and dizziness are the most frequent adverse effects. In this study, we aimed to evaluate the effect of melatonin on daytime sleepiness side effect of gabapentin, sleep quality and pain intensity of patients with neuropathic pain. Methods: Patients suffering from "neuropathic pain" and planed to receive gabapentin therapy were randomly divided into two groups. Group 1 received melatonin 3 mg and gabapentin 900 mg orally, group 2 received matching placebo capsule and gabapentin 900 mg. The Epworth Sleepiness Scale, the Pittsburgh sleep quality index for assessment of sleep quality and Verbal Rating Scale were completed at the 0th, 10th and 30th days of treatment. Additive analgesic drug requirements were recorded. Results: Eighty patients were enrolled to the study; age, gender, ratio of additive analgesic consumption, baseline Epworth Sleepiness Scale, Pittsburg Sleep Quality index and Verbal Rating Scale scores were similar between the groups. Epworth Sleepiness Scale scores, Pittsburgh sleep quality index scores and Verbal Rating Scale scores in Group 1 were significantly lower than group 2 at the 10th day of treatment (p = 0.002, p = 0.003, p = 0.002 respectively). At the 30th day of treatment, Epworth Sleepiness Scale scores and Verbal Rating Scale scores were significantly lower in Group 1 (p = 0.002, p = 0.008 respectively). However, Pittsburgh sleep quality index scores did not significantly differ between the groups (p = 0.0566). Conclusions: Melatonin supplementation rapidly and significantly improved daytime sleepiness side-effect of gabapentin, however sleep quality of the patients with neuropathic pain was similar between groups.

Resumo Justificativa e objetivos: Gabapentina é um agente antiepiléptico, amplamente utilizado para o tratamento da dor neuropática. Embora conhecida por ser bem-tolerada, sonolência e tontura são os seus efeitos adversos mais frequentes. Neste estudo, nosso objetivo foi avaliar o efeito da melatonina sobre o efeito colateral de sonolência diurna da gabapentina, a qualidade do sono e a intensidade da dor em pacientes com dor neuropática. Métodos: Os pacientes que sofriam de "dor neuropática" e com prescrição para receber terapia com gabapentina foram divididos aleatoriamente em dois grupos. O Grupo 1 recebeu 3 mg de melatonina e 900 mg de gabapentina por via oral, o Grupo 2 recebeu uma cápsula de placebo correspondente e 900 mg de gabapentina. A escala de sonolência de Epworth (ESS), o índice de qualidade do sono de Pittsburgh para avaliação da qualidade do sono (PSQI) e a escala de avaliação verbal (VRS) foram aplicados nos dias 0, 10 e 30 de tratamento. A necessidade de medicamentos analgésicos adicionais foi registrada. Resultados: Oitenta pacientes foram incluídos no estudo; idade, sexo, quantidade de analgésico adicional consumida e os escores basais de ESS, PSQI e VRS foram semelhantes entre os grupos. Os escores ESS, PSQI e VRS do Grupo 1 foram significativamente menores que os do Grupo 2 no décimo dia de tratamento (p = 0,002, p = 0,003, p = 0,002, respectivamente). No trigésimo dia de tratamento, os escores ESS e VRS foram significativamente menores no Grupo 1 (p = 0,002, p = 0,008, respectivamente). No entanto, os escores PSQI não diferiram significativamente entre os grupos (p = 0,0566). Conclusões: A suplementação de melatonina melhorou de forma rápida e significativa o efeito colateral de sonolência diurna da gabapentina, mas a qualidade do sono dos pacientes com dor neuropática foi semelhante entre os grupos.

High dose gabapentin does not alter tumor growth in mice but reduces arginase activity and increases superoxide dismutase, IL-6 and MCP-1 levels in Ehrlich ascites.

OBJECTIVES: The purpose of this study was to evaluate the effect of gabapentin on Ehrlich tumor growth in Swiss mice, a highly aggressive and inflammatory tumor model. Mice were grouped into sets of 5 animals and treated from days 2 to 8 with gabapentin 30 mg/kg body weight (G30) or 100 mg/kg body weight (G100), or normal sterile saline (control). RESULTS: The mice were euthanized on day 10. Tumor growth, tumoricidal agents and inflammatory cytokines levels were assessed. At day 10, G30 and G100 mice gained weight, but there were no differences in tumor cell count or in ascites volume. In G100, there was a reduction in arginase and an increase in SOD activities. There was an increase in IL-6 and MCP-1 levels, especially in G100, but no alterations in TNF-α. There was no direct evidence of tumor induction by gabapentin. However, the findings suggest that its use modulates immune response to a more effector and less deleterious profile, with increase in activity of anti-oxidant enzymes and in cytokines that favor activation of macrophages, which could improve the general status of the tumor host.

[Effect of melatonin on the daytime sleepiness side-effect of gabapentin in adults patients with neuropathic pain]. / Efeito da melatonina sobre o efeito colateral de sonolência diurna da gabapentina em pacientes adultos com dor neuropática.

BACKGROUND AND OBJECTIVES: Gabapentin is an antiepileptic drug. Widely used for the management of neuropathic pain. Although it is known to be well tolerated, somnolence and dizziness are the most frequent adverse effects. In this study, we aimed to evaluate the effect of melatonin on daytime sleepiness side effect of gabapentin, sleep quality and pain intensity of patients with neuropathic pain. METHODS: Patients suffering from "neuropathic pain" and planed to receive gabapentin therapy were randomly divided into two groups. Group 1 received melatonin 3mg and gabapentin 900mg orally, group 2 received matching placebo capsule and gabapentin 900mg. The Epworth Sleepiness Scale, the Pittsburgh sleep quality index for assessment of sleep quality and Verbal Rating Scale were completed at the 0th, 10th and 30th days of treatment. Additive analgesic drug requirements were recorded. RESULTS: Eighty patients were enrolled to the study; age, gender, ratio of additive analgesic consumption, baseline Epworth Sleepiness Scale, Pittsburg Sleep Quality index and Verbal Rating Scale scores were similar between the groups. Epworth Sleepiness Scale scores, Pittsburgh sleep quality index scores and Verbal Rating Scale scores in Group 1 were significantly lower than group 2 at the 10th day of treatment (p=0.002, p=0.003, p=0.002 respectively). At the 30th day of treatment, Epworth Sleepiness Scale scores and Verbal Rating Scale scores were significantly lower in Group 1 (p=0.002, p=0.008 respectively). However, Pittsburgh sleep quality index scores did not significantly differ between the groups (p=0.0566). CONCLUSIONS: Melatonin supplementation rapidly and significantly improved daytime sleepiness side-effect of gabapentin, however sleep quality of the patients with neuropathic pain was similar between groups.

Gabapentin in Elastic Liposomes: Preparation, Characterization, Drug Release, and Penetration Through Porcine Skin.

In the outpatient pharmacy compounding, gabapentin, an anti-epileptic agent, has been commonly prescribed to be prepared alone or in combination with other agents in Pluronic lecithin organogel for transdermal pain management and palliative care. The objective of this study was to formulate and characterize gabapentin encapsulated elastic liposomes and then compare the gabapentin-based liposomes with compounded gabapentin-based Pluronic lecithin organogel regarding their efficiency in transdermal delivery of gabapentin. We demonstrated that our small 100-nm unilamellar vesicles of gabapentin encapsulated approximately 6.9 mg/mL Å} 0.2 mg/mL with up to 70% of encapsulation efficiency. Gabapentin released slowly from liposomes over 12 hours while it rapidly released from Pluronic lecithin organogel within 4 hours. We also showed that after 24 hours liposomes significantly accelerated the percutaneous penetration of gabapentin through the porcine skin leading to higher cumulative drug concentrations (~98% of drug permeated with a mean flux of 188.94 µg/cm2/h Å} 42.16 µg/cm2/h) as compared to Pluronic lecithin organogel (~55 % of drug permeated with a mean flux of 56.32 µg/cm2/h Å} 41.93 µg/cm2/h). In conclusion, the elastic liposomal formulation showed higher efficiency than the compounded Pluronic lecithin organogel in the transdermal delivery of gabapentin through porcine skin.

Preoperative pain measures ineffective in outpatient abdominal surgeries.

BACKGROUND: The multimodality addition of preoperative gabapentin, acetaminophen, and celecoxib (GAC) and postoperative TENS has been recommended to diminish narcotics. We predict that GAC-TENS implementation will reduce recovery room time, improve pain control, reduce narcotic refills, and demonstrate usefulness of TENS treatment. METHODS: A prospective study compared a control group of patients not utilizing the GAC-TENS protocol during 2015 to patients using the GAC-TENS protocol during 2016. RESULTS: There was less recovery room time in the control group compared to the protocol group. Postoperative day one pain control was similar between the groups. Less refills were noted. TENS unit satisfaction level was rated "very helpful" by 63% of patients. CONCLUSION: The results call into question the efficacy of the American Pain Society recommendations as they increase time in recovery room but do not decrease the quantity of narcotics used in the recovery room, nor do they improve pain satisfaction responses.