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Pain Physician 2015Individual response to opioid analgesics varies among patients. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Individual response to opioid analgesics varies among patients.
OBJECTIVE
This study sought to clarify the impact of distinct genetic variations on pain, opioid consumption, and opioid side effects in patients with postoperative pain.
STUDY DESIGN
A systematic review and meta-analysis of associations between genetic single-nucleotide polymorphisms (SNPs) and opioids used for acute postoperative pain.
SETTING
This meta-analysis examined all studies involving an association between genetic polymorphisms and the analgesic efficacy or clinical outcome of opioid analgesics for postoperative pain.
METHODS
A literature search was performed up to January 31, 2014, using the PubMed, EMBase, ISI Web of Science, and Cochrane Library databases.
RESULTS
Fifty-nine studies were included in this systematic review, and 23 studies (a total of 5,902 patients) were included in the final meta-analysis. The results showed that human μ-opioid receptor gene (OPRM1) 118G allele variant carriers consumed more opioids for analgesia (SMD = -0.17, 95% CI = [-0.25, -0.10], P < 0.00001), but reported higher pain scores (MD = -0.11, 95% CI = [-0.17, -0.04], P = 0.002) and less nausea and vomiting (odds ratio = 1.30, 95% CI = [1.08, 1.55], P = 0.005) than the homozygous 118AA patients during the first 24 hour but not the 48 hour postoperative period. Moreover, CYP3A4*1G carriers consumed less opioids than homozygous CYP3A4*1/*1 patients during the first 24 hours postoperative period (MD = 45.12, 95% CI = [36.17, 54.06], P < 0.00001). No significant differences were found in CYP3A5*3, ABCB1 C3435T, and G2477T/A genetic polymorphisms.
LIMITATIONS
Some potential non-genetic factors can modify the effects of gene SNP on pain and opioid consumption during the postoperative period, such as age, gender, mood, anxiety, and drug-drug interactions. But further analyses could not be performed in the present meta-analysis due to limited information.
CONCLUSION
The results indicate that among the genetic SNPs we studied which include those affecting analgesic drug metabolism, transport of analgesic agents across the blood-brain barrier, and their activity at target receptors and ion channels and in the modulation of neurotransmitter pathways, the A118G allele variant of OPRM1 has the most potent influence on pain management of postoperative patients. Opioid receptor gene information may provide valuable information for clinicians to properly manage the analgesic use of opioids individually for better pain management.
Topics: Analgesics, Opioid; Female; Genetic Variation; Humans; Male; Middle Aged; Pain Management; Pain, Postoperative; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Receptors, Opioid, mu
PubMed: 25794200
DOI: No ID Found -
Frontiers in Psychiatry 2018Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has... (Review)
Review
Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs. A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018. Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials. These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research.
PubMed: 30140240
DOI: 10.3389/fpsyt.2018.00277 -
Acta Psychiatrica Scandinavica Apr 2022The authors conducted a systematic review and meta-analysis of pharmacological interventions to diminish cognitive side effects of ECT. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The authors conducted a systematic review and meta-analysis of pharmacological interventions to diminish cognitive side effects of ECT.
METHODS
Electronic databases of Pubmed, PsycInfo, Embase and Scopus were searched from inception through 1 April, 2021, using terms for ECT (e.g. electroconvulsive therapy), cognitive outcome (e.g. cogni*) and pharmacological intervention (e.g. calcium channel blocker and general terms, like protein). Original studies with humans receiving ECT were included, which applied pharmacological interventions in comparison with placebo or no additive intervention to diminish cognitive side effects. Data quality was assessed using Risk of Bias and GRADE. Random-effects models were used. PROSPERO registration number was CRD42021212773.
RESULTS
Qualitative synthesis (systematic review) showed 52 studies reporting sixteen pharmacological intervention-types. Quantitative synthesis (meta-analysis) included 26 studies (1387 patients) describing twelve pharmacological intervention-types. Low-quality evidence of efficacy was established for memantine (large effect size) and liothyronine (medium effect size). Very low-quality evidence shows effect of acetylcholine inhibitors, piracetam and melatonin in some cognitive domains. Evidence of no efficacy was revealed for ketamine (very low-quality), herbal preparations with anti-inflammatory properties (very low to low-quality) and opioid receptor agonists (low-quality).
CONCLUSION
Memantine and liothyronine are promising for further research and future application. Quality of evidence was low because of differences in ECT techniques, study populations and cognitive measurements. These findings provide a guide for rational choices of potential pharmacological intervention research targets to decrease the burden of cognitive side effects of ECT. Future research should be more uniform in design and attempt to clarify pathophysiological mechanisms of cognitive side effects of ECT.
Topics: Cognition; Electroconvulsive Therapy; Humans; Ketamine; Memantine; Triiodothyronine
PubMed: 35075641
DOI: 10.1111/acps.13397 -
Biomedicine & Pharmacotherapy =... Oct 2021Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved...
BACKGROUND
Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved with risk of accidental lethal overdosing. With the emergence of accumulating evidence linking genetic variation to opioid response, pharmacogenetic based treatment recommendations have been proposed.
OBJECTIVE
The aim of this review is to evaluate pharmacogenetic evidence and provide an overview on genes involved in the pharmacokinetics and pharmacodynamics of opioids.
METHODS
For this review, a systematic literature search of published articles was used in PubMed®, with no language restriction and between the time period of January 2000 to December 2020. We reviewed randomized clinical studies, study cohorts and case reports that investigated the influence of genetic variants on selected opioid pharmacokinetics and pharmacodynamics. In addition, we reviewed current CPIC clinical recommendations for pharmacogenetic testing.
RESULTS
Results of this review indicate consistent evidence supporting the association between selected genetic variants of CYP2D6 for opioid metabolism. CPIC guidelines include recommendations that indicate the avoidance of tramadol use, in addition to codeine, in CYP2D6 poor metabolizers and ultrarapid metabolizers, and to monitor intermediate metabolizers for less-than-optimal response. While there is consistent evidence for OPRM1 suggesting increased postoperative morphine dosing requirements in A118G G-allele carriers, the clinical relevance remains limited.
CONCLUSION
There is emerging evidence of clinical relevance of CYP2D6 and, to a lesser extent, OPRM1 polymorphism in personalized opioid drug dosing. As a result, first clinics have started to implement pharmacogenetic guidelines for CYP2D6 and codeine.
Topics: Analgesics, Opioid; Animals; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Humans; Pain; Pharmacogenetics; Precision Medicine; Randomized Controlled Trials as Topic; Receptors, Opioid, mu
PubMed: 34523422
DOI: 10.1016/j.biopha.2021.112060 -
The Journal of Pain 2020Chronic postsurgical pain (CPSP) is a significant detriment to postsurgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated... (Meta-Analysis)
Meta-Analysis
Chronic postsurgical pain (CPSP) is a significant detriment to postsurgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated heritability for chronic pain is 45% and that genetic factors partially explain individual susceptibility to CPSP. The aim of this study was to systematically review, assess quality, and summarize the studies in humans that have investigated genetic factors associated with CPSP. We also conducted a meta-analysis to derive a single effect size for evaluable genetic associations with CPSP. Our comprehensive literature search included review of 21 full-text articles evaluating variants of 69 genes for association with CPSP. We found significant gene variant associations reported for variants/haplotypes of 26 genes involved in neurotransmission, pain signaling, immune responses and neuroactive ligand-receptor interaction, with CPSP. Six variants of 5 genes (COMT: rs4680 and rs6269, OPRM1: rs1799971, GCH1: rs3783641, KCNS1: rs734784 and TNFA: rs1800629), were evaluated by more than one study and were included in the meta-analysis. At rs734784 (A>G) of KCNS1, presence of G allele marginally increased risk of CPSP (Additive genetic model; Odds ratio: 1.511; 95% CI 1-2.284; P value: .050), while the other variants did not withstand meta-analyses criteria. Our findings demonstrate the role of genetic factors with different functions in CPSP, and also emphasize that single genetic factors have small effect sizes in explaining complex conditions like CPSP. Heterogeneity in surgical cohorts, population structure, and outcome definitions, as well as small number of available studies evaluating same variants, limit the meta-analysis. There is a need for large-scale, homogenous, replication studies to validate candidate genes, and understand the underlying biological networks underpinning CPSP. PERSPECTIVE: Our systematic review comprehensively describes 21 studies evaluating genetic association with CPSP, and limitations thereof. A meta-analysis of 6 variants (5 genes) found marginally increased risk for CPSP associated with rs734784 A>G of the potassium voltage-gated channel gene (KCNS1). Understanding genetic predisposition for CPSP will enable prediction and personalized management.
Topics: Genetic Predisposition to Disease; Humans; Pain, Postoperative
PubMed: 31129315
DOI: 10.1016/j.jpain.2019.05.008 -
Frontiers in Medicine 2022Myoclonic movement is a very common but undesirable phenomenon during the induction of general anesthesia using etomidate. Such movement may cause unnecessary problems....
BACKGROUND
Myoclonic movement is a very common but undesirable phenomenon during the induction of general anesthesia using etomidate. Such movement may cause unnecessary problems. Currently, there is an increasing number of drugs for preventing etomidate-induced myoclonus (EM). However, direct comparisons of various drugs are lacking, and this interferes with clinical decision-making. Our network meta-analysis (NMA) aimed to compare the efficacy of different drugs for the prevention of moderate-to-severe general myoclonus.
METHODS
Using several biomedical databases, randomized controlled trials (RCTs) published in English from inception to August 22, 2021 were searched. Among the various interventions, we selected nine types of intervention drugs (dexmedetomidine, etomidate, lidocaine, NMDA receptor antagonist, κ opioid receptor agonist, μ opioid receptor agonist, muscle relaxant, gabapentin, and midazolam) for comparison, according to the number of studies. Bayesian NMA was performed using STATA16 and R softwares. The relative risk of EM was assessed using risk ratios (RRs) and the corresponding 95% confidence intervals (CI).
RESULTS
A total of 31 RCTs (3209 patients) were included. NMA results showed that, compared with a placebo, etomidate (RR 4.0, 95%CI 2.1-7.8), κ opioid receptor agonist (RR 2.9, 95%CI 1.9-4.6), μ opioid receptor agonist (RR 3.1, 95%CI 2.3-4.3), NMDA receptor antagonist (RR 1.7, 95%CI 1.0-2.8), dexmedetomidine (RR 2.4, 95%CI 1.5-3.9), lidocaine (RR 2.1, 95%CI 1.2-3.9), and midazolam (RR 2.2, 95%CI 1.5-3.2) can significantly reduce the risk of EM. In contrast, the effects of muscle relaxants (RR 2.1, 95%CI 0.81-5.3) and gabapentin (RR 2.8, 95%CI 0.92-9.3) were inconclusive. Further subgroup analyses showed that preoperative low-dose etomidate, μ-opioid receptor agonist, and κ-opioid receptor agonist were significantly better than other interventions in the prevention of moderate to severe EM.
CONCLUSION
Preoperative use of small doses of etomidate or opioids may be the most effective way to avoid EM, especially moderate and severe EM, which makes anesthesia induction safer, more stable, and aligns better with the requirements of comfortable medicine.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/], [CRD4202127706].
PubMed: 35559341
DOI: 10.3389/fmed.2022.799156 -
Journal of Clinical Medicine Mar 2023In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid... (Review)
Review
In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.
PubMed: 37048572
DOI: 10.3390/jcm12072488 -
Pain Physician Sep 2023Responsiveness to opioid analgesics differs among patients with acute postoperative pain. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Responsiveness to opioid analgesics differs among patients with acute postoperative pain.
OBJECTIVE
Our study presents the most recent evidence on the effect of genetic variations on postoperative pain, opioid consumption, nausea, and vomiting in patients treated with opioids.
STUDY DESIGN
An updated systematic review and meta-analysis on the association between single-nucleotide polymorphisms and opioids administered to patients with acute postoperative pain.
METHODS
PubMed, Embase, ISI Web of Science, and the Cochrane Library databases were searched for articles published from February 1, 2014, through December 31, 2021.
RESULTS
Added to the previous meta-analysis, 39 studies (a total of 7,455 patients) were included in the final meta-analysis. Highlights of the findings include: 1) human μ-opioid receptor gene 118G allele carriers required more opioids during the first postoperative 24 hours (standard mean difference [SMD] = -0.27; 95% CI,-0.40 to -0.14; P < 0.0001) and 48 hours (SMD = -0.52; 95% CI, -0.83 to -0.20; P = 0.001), and reported higher pain scores during the first 24 hours but not at the 48-hour postoperative period (SMD = -0.09, 95% CI, -0.15 to -0.03; P = 0.002) compared to homozygous 118AA patients. 2) patients with the CYP3A4 *1G allele required fewer opioids during the first 24-hour postoperative period (SMD = 0.59; 95% CI, 0.05 to 1.14; P = 0.03) compared to patients with the homozygous CYP3A4*1/*1 allele. 3) Adenosine triphosphate-binding cassette subfamily B member-1 (ABCB1) 3435T allele carriers required more opioids during the 48-hour postoperative period (SMD = -0.21; 95% CI, -0.38 to -0.04; P = 0.02) compared to homozygous CC carriers. 4) Catechol-O-methyl transferase 158A allele carriers required fewer opioids during the first 24-hour postoperative period (SMD = 0.33; 95% CI, 0.15 to 0.51; P = 0.0004) compared to homozygous GG carriers. No significant differences were observed in patients with CYP2D6*10 and ABCB1 G2677A/T genetic polymorphisms.
LIMITATIONS
Several loci were not analyzed in detail due to insufficient clinical data. Furthermore, nongenetic factors that affected analgesic efficacy and the clinical outcome of postoperative pain were not discussed and were not the aim of this meta-analysis.
CONCLUSIONS
In combination with previous systematic reviews and meta-analyses, our results indicate that the A118G allele variant of OPRM1 and the *1*1G allele variant of CYP3A4 have a profound influence on individual differences in opioid reactivity in patients with postoperative pain. Our results, together with the identification of additional single nucleotide polymorphisms in future studies, may provide a theoretical basis for precise clinical analgesia.
KEY WORDS
Single nucleotide polymorphism, postoperative pain, opioid, meta-analysis.
Topics: Humans; Analgesics, Opioid; Catechol O-Methyltransferase; Cytochrome P-450 CYP3A; Pain, Postoperative; Polymorphism, Single Nucleotide
PubMed: 37774182
DOI: No ID Found -
Arthritis Care & Research Oct 2021Opioids have long been prescribed for chronic pain conditions, including osteoarthritis (OA). However, there is little information about their temporal efficacy, or... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Opioids have long been prescribed for chronic pain conditions, including osteoarthritis (OA). However, there is little information about their temporal efficacy, or differences in efficacy and safety between opioids with strong versus weak/intermediate μ opioid receptor-binding affinity. To explore these research questions, we conducted a systematic review and meta-analyses of randomized controlled trials (RCTs) conducted in patients with knee and/or hip OA.
METHODS
We searched Medline, Embase, PubMed Central, and the Cochrane Central Register of Controlled Trials from inception to December 2019 and sought unpublished data. Placebo-controlled RCTs of oral opioids in patients with knee and/or hip OA were included. Standardized mean differences (SMDs) were calculated for pain and function at 2, 4, 8, and 12 weeks. Subgroup analyses for strong and weak/intermediate opioids were conducted. Meta-regression was performed to assess the impact of dosage (morphine equivalency) on pain relief. Risk ratios were calculated for safety at the final follow-up.
RESULTS
A total of 18 RCTs (9,283 participants) were included. Opioids demonstrated small benefits on pain at each time point, with SMDs ranging from -0.28 (95% confidence interval [95% CI] -0.38, -0.17) to -0.19 (95% CI -0.29, -0.08); similar effects were observed for function. Strong opioids demonstrated consistently inferior efficacy and overall worse safety than weak/intermediate opioids. Meta-regression revealed that incremental pain relief achieved beyond 20-50-mg doses was not substantial in the context of increased safety risks.
CONCLUSION
Opioids provide minimal relief of OA symptoms within a 12-week period, and they are known to cause discomfort in a majority of patients. Clinicians and policy makers should reconsider the utility of opioids in the management of OA.
Topics: Aged; Analgesics, Opioid; Arthralgia; Chronic Pain; Female; Humans; Male; Middle Aged; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain Management; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome
PubMed: 32583972
DOI: 10.1002/acr.24363 -
Anesthesiology Research and Practice 2017To summarise the evidence for use of intravenous magnesium for analgesic effect in caesarean section patients. (Review)
Review
OBJECTIVE
To summarise the evidence for use of intravenous magnesium for analgesic effect in caesarean section patients.
BACKGROUND
Postcaesarean pain requires effective analgesia. Magnesium, an -methyl-D-aspartate receptor antagonist and calcium-channel blocker, has previously been investigated for its analgesic properties.
METHODS
A systematic search was conducted of , , , , and databases for randomised-control trials comparing intravenous magnesium to placebo with analgesic outcomes in caesarean patients.
RESULTS
Ten trials met inclusion criteria. Seven were qualitatively compared after exclusion of three for unclear bias risk. Four trials were conducted with general anaesthesia, while three utilised neuraxial anaesthesia. Five of seven trials resulted in decreased analgesic requirement postoperatively and four of seven resulted in lower serial visual analogue scale scores.
CONCLUSIONS
Adjunct analgesic agents are utilised to improve analgesic outcomes and minimise opioid side effects. Preoperative intravenous magnesium may decrease total postcaesarean rescue analgesia consumption with few side effects; however, small sample size and heterogeneity of methodology in included trials restricts the ability to draw strong conclusions. Therefore, given the apparent safety and efficacy of magnesium, its role as an adjunct analgesic in caesarean section patients should be further investigated with the most current anaesthetic techniques.
PubMed: 29333156
DOI: 10.1155/2017/9186374