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Pharmacological Reviews Apr 2018Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes,... (Review)
Review
Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this "disease of pain." Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long-term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na, K, Ca, hyperpolarization-activated cyclic nucleotide-gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first-line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the 2-1 subunit of voltage-gated Ca channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.
Topics: Analgesics; Analgesics, Opioid; Animals; Gabapentin; Humans; Ion Channels; Molecular Targeted Therapy; Neuralgia; Pain Management; Peripheral Nerve Injuries
PubMed: 29500312
DOI: 10.1124/pr.117.014399 -
Pain Practice : the Official Journal of... Jan 2023Gabapentin is a recommended first-line agent for treating neuropathic pain; however, its efficacy rate is reportedly low, and the risk of adverse events is high. A... (Review)
Review
BACKGROUND
Gabapentin is a recommended first-line agent for treating neuropathic pain; however, its efficacy rate is reportedly low, and the risk of adverse events is high. A plausible explanation for this lies with its wide range of actions, the entirety of which have yet to be fully elucidated.
METHODS
A review of the literature was conducted on gabapentin's known and proposed analgesic mechanisms of action, as well as potentially opposing or detrimental actions.
RESULTS
Gabapentin's classical analgesic mechanisms involve direct attenuation of excitatory neurotransmission in the spinal cord via inhibition of neuronal ion channels, while indirect mechanisms include descending inhibition and block of injury-evoked synaptogenesis. Glial effects have also been reported; however, whether they are neuroprotective or detrimental is unknown. Furthermore, data from animal models do not reflect clinical outcomes.
CONCLUSIONS
Gabapentin's clinical use should be reconsidered according to the net effects of its numerous assumed actions, including the tripartite synapse and oligodendrocyte effects. Whether it is doing more harm than good, especially in the scenarios of incomplete or loss of response, warrants consideration when prescribing gabapentin.
Topics: Animals; Gabapentin; gamma-Aminobutyric Acid; Amines; Cyclohexanecarboxylic Acids; Analgesics
PubMed: 36300903
DOI: 10.1111/papr.13165 -
The Canadian Veterinary Journal = La... Sep 2021This review focuses on pre-appointment medications used to decrease fear and anxiety in dogs and cats related to veterinary visits. A review of the literature revealed... (Review)
Review
This review focuses on pre-appointment medications used to decrease fear and anxiety in dogs and cats related to veterinary visits. A review of the literature revealed data on 4 medications from 4 medication classes that have been used to ameliorate acute situational fear and anxiety in dogs and cats: gabapentin, trazodone, oral transmucosal dexmedetomidine, and alprazolam. The available information on use, mechanism of action, and pharmacokinetics is reviewed.
Topics: Animals; Anxiety; Cat Diseases; Cats; Dog Diseases; Dogs; Fear; Gabapentin
PubMed: 34475580
DOI: No ID Found -
Molecular Psychiatry Mar 2022The gabapentinoids, gabapentin, and pregabalin, target the αδ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become... (Meta-Analysis)
Meta-Analysis
The gabapentinoids, gabapentin, and pregabalin, target the αδ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.
Topics: Amines; Anxiety; Bipolar Disorder; Calcium Channels; Cyclohexanecarboxylic Acids; Gabapentin; Humans; Pregabalin; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; gamma-Aminobutyric Acid
PubMed: 34819636
DOI: 10.1038/s41380-021-01386-6 -
Nature May 2023Gliomas synaptically integrate into neural circuits. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal...
Gliomas synaptically integrate into neural circuits. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.
Topics: Humans; Brain; Brain Neoplasms; Glioblastoma; Neural Pathways; Thrombospondin 1; Gabapentin; Disease Progression; Cognition; Survival Rate; Wakefulness; Biopsy; Cell Proliferation
PubMed: 37138086
DOI: 10.1038/s41586-023-06036-1 -
Neurologia Oct 2022Phantom limb pain (PLP) is a type of neuropathic pain that affects the territory of an amputated limb or other surgically removed body parts. Between 60% and 90% of... (Review)
Review
INTRODUCTION
Phantom limb pain (PLP) is a type of neuropathic pain that affects the territory of an amputated limb or other surgically removed body parts. Between 60% and 90% of amputees suffer from PLP during follow-up. There are a range of therapeutic options for PLP, both pharmacological (gabapentin, amitriptyline, tricyclic antidepressants, etc) and non-pharmacological (transcutaneous electrical nerve stimulation, hypnosis, acupuncture, etc). A widely accepted hypothesis considers PLP to be the consequence of postamputation cortical reorganisation. New treatment approaches, such as mirror therapy (MT), have been developed as a result of Ramachandran's groundbreaking research in the 1990s. This review analyses the current evidence on the efficacy of MT for treating PLP.
DEVELOPMENT
We performed a literature review of publications registered from 2012 to 2017 on the CINAHL, Cochrane, Scopus, and PubMed (including Medline) databases using the descriptors "phantom limb" and "mirror therapy." We identified 115 publications addressing MT in PLP. Of these, 17 (15%) contributed useful information for pooled analysis.
CONCLUSIONS
MT seems to be effective in relieving PLP, reducing the intensity and duration of daily pain episodes. It is a valid, simple, and inexpensive treatment for PLP. The methodological quality of most publications in this field is very limited, highlighting the need for additional, high-quality studies to develop clinical protocols that could maximise the benefits of MT for patients with PLP.
Topics: Amitriptyline; Antidepressive Agents, Tricyclic; Gabapentin; Humans; Mirror Movement Therapy; Phantom Limb
PubMed: 36195376
DOI: 10.1016/j.nrleng.2018.08.005 -
JAMA Internal Medicine May 2020Although an estimated 30 million people meet criteria for alcohol use disorder (AUD), few receive appropriate pharmacotherapy. A more personalized, symptom-specific,... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Although an estimated 30 million people meet criteria for alcohol use disorder (AUD), few receive appropriate pharmacotherapy. A more personalized, symptom-specific, approach might improve efficacy and acceptance.
OBJECTIVE
To examine whether gabapentin would be useful in the treatment of AUD, especially in those with the most alcohol withdrawal symptoms.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind randomized clinical trial conducted between November 2014 and June 2018 evaluated gabapentin vs placebo in community-recruited participants screened and treated in an academic outpatient setting over a 16-week treatment period. A total of 145 treatment-seeking individuals who met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for AUD and were not receiving other AUD intervention were screened, and 96 who also met recent alcohol withdrawal criteria were randomized to treatment after 3 abstinent days. Daily drinking was recorded, and percentage of disialo carbohydrate-deficient transferrin in the blood, a heavy drinking marker, was collected at baseline and monthly during treatment.
INTERVENTIONS
Gabapentin up to 1200 mg/d, orally, vs placebo along with 9 medical management visits (20 minutes each).
MAIN OUTCOMES AND MEASURES
The percentage of individuals with no heavy drinking days and those with total abstinence were compared between treatment groups and further evaluated based on prestudy alcohol withdrawal symptoms.
RESULTS
Of 96 randomized individuals, 90 were evaluable (44 in the gabapentin arm and 46 in the placebo arm), with a mean (SD) age of 49.6 (10.1) years; 69 were men (77%) and 85 were white (94%). The evaluable participants had 83% baseline heavy drinking days (4 or more drinks/day for women, 5 or more for men) and met 4.5 alcohol withdrawal criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). More gabapentin-treated individuals had no heavy drinking days (12 of 44 participants [27%]) compared with placebo (4 of 46 participants [9%]), a difference of 18.6% (95% CI, 3.1-34.1; P = .02; number needed to treat [NNT], 5.4), and more total abstinence (8 of 44 [18%]) compared with placebo (2 of 46 [4%]), a difference of 13.8% (95% CI, 1.0-26.7; P = .04; NNT, 6.2). The prestudy high-alcohol withdrawal group had positive gabapentin effects on no heavy drinking days (P < .02; NNT, 3.1) and total abstinence (P = .003; NNT, 2.7) compared with placebo, while within the low-alcohol withdrawal group, there were no significant differences. These findings were similar for other drinking variables, where gabapentin was more efficacious than placebo in the high-alcohol withdrawal group only. Gabapentin caused more dizziness, but this did not affect efficacy.
CONCLUSIONS AND RELEVANCE
These data, combined with others, suggest gabapentin might be most efficacious in people with AUD and a history of alcohol withdrawal symptoms. Future studies should evaluate sleep changes and mood during early recovery as mediators of gabapentin efficacy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02349477.
Topics: Adult; Alcohol Abstinence; Alcoholism; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Gabapentin; Humans; Male; Middle Aged; Substance Withdrawal Syndrome; Treatment Outcome
PubMed: 32150232
DOI: 10.1001/jamainternmed.2020.0249 -
British Journal of Anaesthesia Dec 2022Preemptive analgesia may improve postoperative pain management, but the optimal regimen is unclear. This study aimed to compare the effects and adverse events of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preemptive analgesia may improve postoperative pain management, but the optimal regimen is unclear. This study aimed to compare the effects and adverse events of preemptive analgesia on postoperative pain and opioid consumption.
METHODS
In this network meta-analysis, 19 preemptive analgesia regimens were compared. Two authors independently searched databases, selected studies, and extracted data. Primary outcomes were the intensity of postoperative pain and opioid consumption. Secondary outcomes included the time to first analgesia rescue and incidence of postoperative nausea or vomiting (PONV).
RESULTS
In total, 188 studies were included (13 769 subjects). Ten of 19 regimens reduced postoperative pain intensity compared with placebo, with mean differences 100-point scale ranging from -4.79 (95% confidence interval [CI]: -8.61 to -0.96.) for gabapentin at 48 h to -21.99 (95% CI: -36.97 to -7.02) for lornoxicam at 6 h. Eight regimens reduced opioid consumption compared with placebo, with mean differences ranging from -0.48 mg (95% CI: -0.89 to -0.08) i.v. milligrams of morphine equivalents (IMME) for acetaminophen at 12 h to -2.27 IMME (95% CI: -3.07 to -1.46) for ibuprofen at 24 h. Five regimens delayed rescue analgesia from 1.75 (95% CI: 0.59-2.91) h for gabapentin to 7.35 (95% CI: 3.66-11.04) h for epidural analgesia. Five regimens had a lower incidence of PONV compared with placebo, ranging from an odds ratio of 0.22 (95% CI: 0.11-0.42) for ibuprofen to 0.59 (95% CI: 0.40-0.87) for pregabalin.
CONCLUSIONS
Use of preemptive analgesia reduces postoperative pain, opioid consumption, and postoperative nausea or vomiting, and delays rescue analgesia.
SYSTEMATIC REVIEW PROTOCOL
PROSPERO CRD42021232593.
Topics: Humans; Analgesia, Epidural; Analgesics, Opioid; Gabapentin; Ibuprofen; Network Meta-Analysis; Pain, Postoperative; Postoperative Nausea and Vomiting
PubMed: 36404458
DOI: 10.1016/j.bja.2022.08.038 -
European Journal of Internal Medicine Nov 2020Cough is a common respiratory symptom that is considered to be chronic when it lasts more than eight weeks. When severe, chronic cough may significantly impact an... (Review)
Review
Cough is a common respiratory symptom that is considered to be chronic when it lasts more than eight weeks. When severe, chronic cough may significantly impact an individual's quality of life, and such patients are frequently referred for specialist evaluation. Current international guidelines provide algorithms for the management of chronic cough: in most cases, treatment of the underlying disease is sufficient to improve or resolve cough symptoms. Severe chronic cough may significantly affect patients' quality of life and necessitate frequent referral for specialist evaluations. In this narrative review, we summarize non-pharmacologic and pharmacologic management of adult patients with chronic cough of known cause that persists after proper treatment (chronic refractory cough, CRC) or chronic cough of unknown cause in adult patients. If chronic cough persists even after treatment of the underlying disease, or if the chronic cough is not attributable to any cause, then a symptomatic approach with neuromodulators may be considered, with gabapentin as the first choice, and opioids or macrolides as alternatives. Speech pathology treatment and/or neuromodulators should be discussed with patients and alternative options carefully considered, taking into account risk/benefit. Novel promising drugs are under investigation (e.g. P2×3 inhibitors), but additional studies are needed in this field. Speech pathology can be combined with a neuromodulator to give an enhanced treatment response of longer duration suggesting that non-pharmacologic treatment may play a key role in the management of CRC.
Topics: Adult; Asthma; Chronic Disease; Cough; Gabapentin; Humans; Quality of Life
PubMed: 32958373
DOI: 10.1016/j.ejim.2020.09.008 -
Atencion Primaria Jan 2022This SR aims to assess the effectiveness of pregabalin and gabapentin on pain and disability caused by acute sciatica and the adverse events associated with their... (Meta-Analysis)
Meta-Analysis
AIM
This SR aims to assess the effectiveness of pregabalin and gabapentin on pain and disability caused by acute sciatica and the adverse events associated with their clinical use.
DESIGN
Systematic review.
DATABASES
Electronic databases of Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Clinical Trials.gov were searched from their inception until March 1st of 2021.
SELECTION CRITERIA
Randomized trials (RCT) with adults>18 years old with acute sciatica for a minimum of 1 week and a maximum of 1 year (at least moderate pain).
DATA TREATMENT
The outcomes were pain, disability and adverse events. Data was summarized using odds ratio and mean difference. GRADE was used to calculate the level of evidence.
RESULTS
Eight RCT involving 747 participants were included. The effect of pregabalin was assessed in 3 RCT and in one three-arm trial (pregabalin vs limaprost vs a combination of limaprost and pregabalin). Two trials assessed the effect of gabapentin compared with placebo and one compared with tramadol. One study assessed the effect of gabapentin vs pregabalin in a crossover head-to-head trial. A statistically significant improvement on leg pain at 2 weeks and leg pain with movement at 3 and 4 months was found in a RCT comparing gabapentin with placebo. There were no statistically differences on the remaining time periods assessed for leg pain, low back pain and functional disability.
CONCLUSIONS
This SR provides clear evidence for lack of effectiveness of pregabalin and gabapentin for sciatica pain management. In view of this, its routine clinical use cannot be supported.
Topics: Adolescent; Adult; Analgesics; Gabapentin; Humans; Low Back Pain; Pregabalin; Sciatica
PubMed: 34637958
DOI: 10.1016/j.aprim.2021.102144