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British Journal of Anaesthesia Jun 2019Opioid-induced hyperalgesia (OIH) is well documented in preclinical studies, but findings of clinical studies are less consistent. The objective was to undertake a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Opioid-induced hyperalgesia (OIH) is well documented in preclinical studies, but findings of clinical studies are less consistent. The objective was to undertake a systematic review and meta-analysis of studies examining evidence for OIH in humans after opioid exposure.
METHODS
Systematic electronic searches utilised six research databases (Embase, Medline, PubMed, CINAHL Plus, Web of Science, and OpenGrey). Manual 'grey' literature searches were also undertaken. The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was used to develop search strategies, and findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Data synthesis and subgroup analyses were undertaken using a random effects model (DerSimonian-Laird method).
RESULTS
A total of 6167 articles were identified. After abstract and full-text reviews, 26 articles (involving 2706 participants) were included in the review. There was evidence of OIH, assessed by pain tolerance, in response to noxious thermal (hot and cold) stimuli, but not electrical stimuli. There was no evidence of OIH when assessing pain detection thresholds. OIH was more evident in patients with opioid use disorder than in patients with pain, and in patient groups treated with N-methyl-d-aspartate receptor antagonists (primarily evidenced in methadone-maintained populations).
CONCLUSIONS
OIH was evident in patients after chronic opioid exposure, but findings were dependent upon pain modality and assessment measures. Further studies should consider evaluating both pain threshold and pain tolerance across a range of modalities to ensure assessment validity. Significant subgroup findings suggest that potential confounders of pain judgements, such as illicit substance use, affective characteristics, or coping styles, should be rigorously controlled in future studies.
Topics: Analgesics, Opioid; Chronic Pain; Drug Administration Schedule; Humans; Hyperalgesia; Pain Measurement; Pain Threshold
PubMed: 30915985
DOI: 10.1016/j.bja.2018.09.019 -
Anaesthesia May 2019Opioids are administered peri-operatively for postoperative analgesia, and intra-operatively to control the sympathetic response to surgical stimuli, frequently as a... (Meta-Analysis)
Meta-Analysis
Opioids are administered peri-operatively for postoperative analgesia, and intra-operatively to control the sympathetic response to surgical stimuli, frequently as a surrogate for presumed pain. However, opioid use during surgery is a matter of dispute in contemporary practice and carries the risk of side-effects such as postoperative nausea and vomiting. This meta-analysis investigated whether opioid-inclusive, compared with opioid-free anaesthesia, would reduce postoperative pain, without increasing the rate of postoperative nausea and vomiting. The electronic databases Medline and PubMed were searched until June 2018. We included trials investigating pain outcomes and comparing any type of intra-operative opioid administration with placebo injection or no intra-operative opioid. Most meta-analyses were performed using a random effects model. We rated the quality of evidence for each outcome. The primary outcome was pain score at rest (analogue scale, 0-10) at two postoperative hours. Our secondary outcomes included the rate of postoperative nausea and vomiting within the first 24 postoperative hours and length of stay in the recovery area. Twenty-three randomised controlled trials, including 1304 patients, were identified. Pain scores at rest at two postoperative hours were equivalent in the opioid-inclusive and opioid-free groups with a mean difference (95%CI) of 0.2 (-0.2 to 0.5), I = 83%, p = 0.38 and a high quality of evidence. Similarly, there was high-quality evidence that the rate of postoperative nausea and vomiting was reduced in the opioid-free group, with a risk ratio (95%CI) of 0.77 (0.61-0.97), I = 16%, p = 0.03 and high-quality evidence for a similar length of stay in the recovery area, the mean difference (95%CI) being 0.6 (-8.2 to 9.3), min, I = 60%, p = 0.90. As there is strong evidence that opioid-inclusive anaesthesia does not reduce postoperative pain, but is associated with more postoperative nausea and vomiting, when compared with opioid-free anaesthesia, we suggest that anaesthetists should reconsider their intra-operative opioid choices on a case-by-case basis.
Topics: Analgesics, Opioid; Anesthesia, General; Drug Administration Schedule; Humans; Intraoperative Care; Pain, Postoperative; Postoperative Nausea and Vomiting
PubMed: 30802933
DOI: 10.1111/anae.14582 -
The Journal of Pain Aug 2019Learning processes have been discussed in the context of pain chronicity for decades. Particularly, operant conditioning has been used to experimentally induce and... (Meta-Analysis)
Meta-Analysis
Learning processes have been discussed in the context of pain chronicity for decades. Particularly, operant conditioning has been used to experimentally induce and modulate pain in healthy humans. In this systematic review and meta-analysis, research findings on pain facilitation (hyperalgesic effect) and pain elicitation (allodynic effect) are evaluated. The review was performed according to the PRISMA guideline and an a priori published protocol. Nine databases were searched for relevant publications: PubMed, Cochrane Register of Controlled Trials (CENTRAL), Web of Science, ScienceDirect, EBSCO, PsycINFO, MEDLINE, PsycARTICLES, and CINAHL. Studies were included if they investigated pain-free humans, exposed to an operant conditioning procedure of pain. Two independent assessors screened publications against eligibility criteria and assessed the risk of bias with the Cochrane risk of bias scale. A total of 3155 records were screened, of which 8 were included in the qualitative (401 participants) and 5 into the quantitative (110 participants) synthesis. Results showed that hyperalgesic (standardized mean difference = -0.80, 95% confidence interval = -1.33 to -0.27, P = .003) and allodynic effects (standardized mean difference = -1.27, 95% confidence interval = -2.46 to -0.08, P = .04) can be induced in healthy humans, indicating that pain can be shaped by contingencies of reinforcement. However, the uncertainty of the effect is relatively high, mostly owing to the small number of included studies, demand characteristics, and the risk of bias. This is especially relevant for studies on allodynic effects where the decrease in nociception should be more rigorously controlled. PERSPECTIVE: Operant conditioning can be a mechanism of pain chronicity. All experimental studies investigating this hypothesis have been identified and summarized. It has been demonstrated that allodynic and hyperalgesic effects can be induced by operant conditioning.
Topics: Chronic Pain; Conditioning, Operant; Humans; Hyperalgesia; Randomized Controlled Trials as Topic; Reinforcement, Psychology
PubMed: 30690165
DOI: 10.1016/j.jpain.2019.01.009 -
The Cochrane Database of Systematic... Dec 2018Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may enhance conventional analgesics in the acute postoperative setting.
OBJECTIVES
To evaluate the efficacy and safety of perioperative intravenous ketamine in adult patients when used for the treatment or prevention of acute pain following general anaesthesia.
SEARCH METHODS
We searched CENTRAL, MEDLINE and Embase to July 2018 and three trials registers (metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)) together with reference checking, citation searching and contact with study authors to identify additional studies.
SELECTION CRITERIA
We sought randomised, double-blind, controlled trials of adults undergoing surgery under general anaesthesia and being treated with perioperative intravenous ketamine. Studies compared ketamine with placebo, or compared ketamine plus a basic analgesic, such as morphine or non-steroidal anti-inflammatory drug (NSAID), with a basic analgesic alone.
DATA COLLECTION AND ANALYSIS
Two review authors searched for studies, extracted efficacy and adverse event data, examined issues of study quality and potential bias, and performed analyses. Primary outcomes were opioid consumption and pain intensity at rest and during movement at 24 and 48 hours postoperatively. Secondary outcomes were time to first analgesic request, assessment of postoperative hyperalgesia, central nervous system (CNS) adverse effects, and postoperative nausea and vomiting. We assessed the evidence using GRADE and created a 'Summary of findings' table.
MAIN RESULTS
We included 130 studies with 8341 participants. Ketamine was given to 4588 participants and 3753 participants served as controls. Types of surgery included ear, nose or throat surgery, wisdom tooth extraction, thoracotomy, lumbar fusion surgery, microdiscectomy, hip joint replacement surgery, knee joint replacement surgery, anterior cruciate ligament repair, knee arthroscopy, mastectomy, haemorrhoidectomy, abdominal surgery, radical prostatectomy, thyroid surgery, elective caesarean section, and laparoscopic surgery. Racemic ketamine bolus doses were predominantly 0.25 mg to 1 mg, and infusions 2 to 5 µg/kg/minute; 10 studies used only S-ketamine and one only R-ketamine. Risk of bias was generally low or uncertain, except for study size; most had fewer than 50 participants per treatment arm, resulting in high heterogeneity, as expected, for most analyses. We did not stratify the main analysis by type of surgery or any other factor, such as dose or timing of ketamine administration, and used a non-stratified analysis.Perioperative intravenous ketamine reduced postoperative opioid consumption over 24 hours by 8 mg morphine equivalents (95% CI 6 to 9; 19% from 42 mg consumed by participants given placebo, moderate-quality evidence; 65 studies, 4004 participants). Over 48 hours, opioid consumption was 13 mg lower (95% CI 10 to 15; 19% from 67 mg with placebo, moderate-quality evidence; 37 studies, 2449 participants).Perioperative intravenous ketamine reduced pain at rest at 24 hours by 5/100 mm on a visual analogue scale (95% CI 4 to 7; 19% lower from 26/100 mm with placebo, high-quality evidence; 82 studies, 5004 participants), and at 48 hours by 5/100 mm (95% CI 3 to 7; 22% lower from 23/100 mm, high-quality evidence; 49 studies, 2962 participants). Pain during movement was reduced at 24 hours (6/100 mm, 14% lower from 42/100 mm, moderate-quality evidence; 29 studies, 1806 participants), and 48 hours (6/100 mm, 16% lower from 37 mm, low-quality evidence; 23 studies, 1353 participants).Results for primary outcomes were consistent when analysed by pain at rest or on movement, operation type, and timing of administration, or sensitivity to study size and pain intensity. No analysis by dose was possible. There was no difference when nitrous oxide was used. We downgraded the quality of the evidence once if numbers of participants were large but small-study effects were present, or twice if numbers were small and small-study effects likely but testing not possible.Ketamine increased the time for the first postoperative analgesic request by 54 minutes (95% CI 37 to 71 minutes), from a mean of 39 minutes with placebo (moderate-quality evidence; 31 studies, 1678 participants). Ketamine reduced the area of postoperative hyperalgesia by 7 cm² (95% CI -11.9 to -2.2), compared with placebo (very low-quality evidence; 7 studies 333 participants). We downgraded the quality of evidence because of small-study effects or because the number of participants was below 400.CNS adverse events occurred in 52 studies, while 53 studies reported of absence of CNS adverse events. Overall, 187/3614 (5%) participants receiving ketamine and 122/2924 (4%) receiving control treatment experienced an adverse event (RR 1.2, 95% CI 0.95 to 1.4; high-quality evidence; 105 studies, 6538 participants). Ketamine reduced postoperative nausea and vomiting from 27% with placebo to 23% with ketamine (RR 0.88, 95% CI 0.81 to 0.96; the number needed to treat to prevent one episode of postoperative nausea and vomiting with perioperative intravenous ketamine administration was 24 (95% CI 16 to 54; high-quality evidence; 95 studies, 5965 participants).
AUTHORS' CONCLUSIONS
Perioperative intravenous ketamine probably reduces postoperative analgesic consumption and pain intensity. Results were consistent in different operation types or timing of ketamine administration, with larger and smaller studies, and by higher and lower pain intensity. CNS adverse events were little different with ketamine or control. Perioperative intravenous ketamine probably reduces postoperative nausea and vomiting by a small extent, of arguable clinical relevance.
Topics: Acute Pain; Adult; Analgesics; Analgesics, Opioid; Central Nervous System Diseases; Humans; Hyperalgesia; Injections, Intravenous; Ketamine; Morphine; Pain Measurement; Pain, Postoperative; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic
PubMed: 30570761
DOI: 10.1002/14651858.CD012033.pub4 -
JAMA Psychiatry Nov 2018Cannabinoid drugs are widely used as analgesics, but experimental pain studies have produced mixed findings. The analgesic properties of cannabinoids remain unclear. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Cannabinoid drugs are widely used as analgesics, but experimental pain studies have produced mixed findings. The analgesic properties of cannabinoids remain unclear.
OBJECTIVE
To conduct a systematic review and meta-analysis of the association between cannabinoid drug administration and experimental pain outcomes in studies of healthy adults.
DESIGN, SETTING, AND PARTICIPANTS
A systematic search of PubMed, EMBASE, MEDLINE, PsycINFO, and CINAHL was conducted from the inception of each database to September 30, 2017. Studies were eligible for inclusion if they met criteria, including healthy participants and an experimentally controlled administration of any cannabinoid preparation in a quantified dose. Studies that used participants with chronic pain were excluded. Data extracted included study characteristics, cannabinoid types and doses, sex composition, and outcomes. Study quality was assessed using a validity measure previously established in published reviews. Random-effects meta-analyses were used to pool data and generate summary estimates.
MAIN OUTCOMES AND MEASURES
Experimental pain threshold, pain tolerance, pain intensity, pain unpleasantness, and mechanical hyperalgesia.
RESULTS
Eighteen placebo-controlled studies (with 442 participants) were identified. Of the 442 participants, 233 (52.7%) were male and 209 (47.3%) were female. For sample ages, 13 (72%) of the 18 studies reported a mean sample age (26.65 years), 4 (22%) reported a range, and 1 (6%) reported a median value. The search yielded sufficient data to analyze 18 pain threshold comparisons, 22 pain intensity comparisons, 9 pain unpleasantness comparisons, 13 pain tolerance comparisons, and 9 mechanical hyperalgesia comparisons. Cannabinoid administration was associated with small increases in pain threshold (Hedges g = 0.186; 95% CI, 0.054-0.318; P = .006), small to medium increases in pain tolerance (Hedges g = 0.225; 95% CI, 0.015-0.436; P = .04), and a small to medium reduction in the unpleasantness of ongoing experimental pain (Hedges g = 0.288; 95% CI, 0.104-0.472; P = .002). Cannabinoid administration was not reliably associated with a decrease in experimental pain intensity (Hedges g = 0.017; 95% CI, -0.120 to 0.154; P = .81) or mechanical hyperalgesia (Hedges g = 0.093; 95% CI, -0.059 to 0.244; P = .23). The mean quality rating across studies was good.
CONCLUSIONS AND RELEVANCE
Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced; instead, cannabinoids may make experimental pain feel less unpleasant and more tolerable, suggesting an influence on affective processes. Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain.
Topics: Adult; Analgesics; Cannabinoids; Female; Humans; Male; Pain; Pain Measurement; Pain Threshold
PubMed: 30422266
DOI: 10.1001/jamapsychiatry.2018.2503 -
Frontiers in Pharmacology 2018Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been postulated as an adjuvant analgesic for preventing remifentanil-induced hyperalgesia after...
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been postulated as an adjuvant analgesic for preventing remifentanil-induced hyperalgesia after surgery. This systematic review and meta-analysis aims to assess the effectiveness of ketamine [racemic mixture and -(+)-ketamine] in reducing morphine consumption and pain intensity scores after remifentanil-based general anesthesia. We performed a literature search of the PubMed, Web of Science, Scopus, Cochrane, and EMBASE databases in June 2017 and selected randomized controlled trials using predefined inclusion and exclusion criteria. To minimize confounding and heterogeneity, studies of NMDA receptor antagonists other than ketamine were excluded and the selected studies were grouped into those assessing minor or major surgery. Methodological quality was evaluated with the PEDro and JADA scales. The data were extracted and meta-analyses were performed where possible. Twelve RCTs involving 156 adults who underwent minor surgery and 413 adults who underwent major surgery were included in the meta-analysis. When used as an adjuvant to morphine, ketamine reduced postoperative morphine consumption in the first 24 h and postoperative pain intensity in the first 2 h in the minor and major surgery groups. It was also associated with significantly reduced pain intensity in the first 24 h in the minor surgery group. Time to the first rescue analgesia was longer in patients who received ketamine and underwent major surgery. No significant differences in the incidence of ketamine-related adverse effects were observed among patients in the intervention group and controls. This systematic review and meta-analysis show that low-dose (≤0.5 mg/kg for iv bolus or ≤5 μg/kg/min for iv perfusion) of ketamine reduces postoperative morphine consumption and pain intensity without increasing the incidence of adverse effects.
PubMed: 30174603
DOI: 10.3389/fphar.2018.00921 -
PLoS Neglected Tropical Diseases Jun 2018Chikungunya virus (CHIKV) is an emerging arboviral infection with a global distribution and may cause fetal and neonatal infections after maternal CHIKV-infections... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chikungunya virus (CHIKV) is an emerging arboviral infection with a global distribution and may cause fetal and neonatal infections after maternal CHIKV-infections during gestation.
METHODOLOGY
We performed a systematic review to evaluate the risk for: a) mother-to-child transmission (MTCT), b) antepartum fetal deaths (APFD), c) symptomatic neonatal disease, and d) neonatal deaths from maternal CHIKV-infections during gestation. We also recorded the neonatal clinical manifestations after such maternal infections (qualitative data synthesis). We searched PubMed (last search 3/2017) for articles, of any study design, with any of the above outcomes. We calculated the overall risk of MTCT, APFDs and risk of symptomatic neonatal disease by simple pooling. For endpoints with ≥5 events in more than one study, we also synthesized the data by random-effect-model (REM) meta-analysis.
PRINCIPAL FINDINGS
Among 563 identified articles, 13 articles from 8 cohorts were included in the quantitative data synthesis and 33 articles in the qualitative data synthesis. Most cohorts reported data only on symptomatic rather than on all neonatal infections. By extrapolation also of these data, the overall pooled-MTCT-risk across cohorts was at least 15.5% (206/1331), (12.6% by REMs). The pooled APFD-risk was 1.7% (20/1203); while the risk of CHIKV-confirmed-APFDs was 0.3% (3/1203). Overall, the pooled-risk of symptomatic neonatal disease was 15.3% (203/1331), (11.9% by REMs). The pooled risk of symptomatic disease was 50.0% (23/46) among intrapartum vs 0% (0/712) among antepartum/peripartum maternal infections. Infected newborns, from maternal infections during gestation were either asymptomatic or presented within their first week of life, but not at birth, with fever, irritability, hyperalgesia, diffuse limb edema, rashes and occasionally sepsis-like illness and meningoencephalitis. The pooled-risk of neonatal death was 0.6% (5/832) among maternal infections and 2.8% (5/182) among neonatal infections; long-term neurodevelopmental delays occurred in 50% of symptomatic neonatal infections.
CONCLUSIONS/SIGNIFICANCE
Published cohorts with data on the risk to the fetus and/or newborn from maternal CHIKV-infections during gestation were sparse compared to the number of recently reported CHIKV-infection outbreaks worldwide; however perinatal infections do occur, at high rates during intrapartum period, and can be related to neonatal death and long-term disabilities.
Topics: Chikungunya Fever; Chikungunya virus; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infectious Disease Transmission, Vertical; Male; Pregnancy; Pregnancy Complications, Infectious
PubMed: 29897898
DOI: 10.1371/journal.pntd.0006510 -
Scientific Reports Jan 2018There are considerable disagreements on the application of olfactory ensheathing cells (OEC) for spinal cord injury (SCI) rehabilitation. The present meta-analysis was... (Meta-Analysis)
Meta-Analysis Review
There are considerable disagreements on the application of olfactory ensheathing cells (OEC) for spinal cord injury (SCI) rehabilitation. The present meta-analysis was designed to investigate the efficacy of OEC transplantation on motor function recovery and neuropathic pain alleviation in SCI animal models. Accordingly, all related studies were identified and included. Two independent researchers assessed the quality of the articles and summarized them by calculating standardized mean differences (SMD). OEC transplantation was shown to significantly improve functional recovery (SMD = 1.36; 95% confidence interval: 1.05-1.68; p < 0.001). The efficacy of this method was higher in thoracic injuries (SMD = 1.41; 95% confidence interval: 1.08-1.74; p < 0.001) and allogeneic transplants (SMD = 1.53; 95% confidence interval: 1.15-1.90; p < 0.001). OEC transplantation had no considerable effects on the improvement of hyperalgesia (SMD = -0.095; 95% confidence interval: -0.42-0.23; p = 0.57) but when the analyses were limited to studies with follow-up ≥8 weeks, it was associated with increased hyperalgesia (SMD = -0.66; 95% confidence interval: -1.28-0.04; p = 0.04). OEC transplantation did not affect SCI-induced allodynia (SMD = 0.54; 95% confidence interval: -0.80-1.87; p = 0.43). Our findings showed that OEC transplantation can significantly improve motor function post-SCI, but it has no effect on allodynia and might lead to relative aggravation of hyperalgesia.
Topics: Animals; Cell Transplantation; Humans; Neuralgia; Olfactory Bulb; Olfactory Mucosa; Spinal Cord Injuries
PubMed: 29321494
DOI: 10.1038/s41598-017-18754-4 -
Journal of Pain Research 2017The present review investigated whether there are systematic sex differences in the placebo and the nocebo effect. (Review)
Review
OBJECTIVES
The present review investigated whether there are systematic sex differences in the placebo and the nocebo effect.
METHODS
A literature search was conducted in multiple electronic databases. Studies were included if the study compared a group or condition where a placebo was administered to a natural history group or similar cohort.
RESULTS
Eighteen studies were identified - 12 on placebo effects and 6 on nocebo effects. Chi-square tests revealed that 1) males responded more strongly to placebo treatment, and females responded more strongly to nocebo treatment, and 2) males responded with larger placebo effects induced by verbal information, and females responded with larger nocebo effects induced by conditioning procedures.
CONCLUSION
This review indicates that there are sex differences in the placebo and nocebo effects, probably caused by sex differences in stress, anxiety, and the endogenous opioid system.
PubMed: 28831271
DOI: 10.2147/JPR.S134745 -
Ageing Research Reviews May 2017While hyperalgesia (increased pain sensitivity) has been suggested to contribute to the increased prevalence of clinical pain in Parkinson's disease (PD), experimental... (Meta-Analysis)
Meta-Analysis Review
While hyperalgesia (increased pain sensitivity) has been suggested to contribute to the increased prevalence of clinical pain in Parkinson's disease (PD), experimental research is equivocal and mechanisms are poorly understood. We conducted a meta-analysis of studies comparing PD patients to healthy controls (HCs) in their response to experimental pain stimuli. Articles were acquired through systematic searches of major databases from inception until 10/2016. Twenty-six studies met inclusion criteria, comprising 1292 participants (PD=739, HCs=553). Random effects meta-analysis of standardized mean differences (SMD) revealed lower pain threshold (indicating hyperalgesia) in PD patients during unmedicated OFF states (SMD=0.51) which was attenuated during dopamine-medicated ON states (SMD=0.23), but unaffected by age, PD duration or PD severity. Analysis of 6 studies employing suprathreshold stimulation paradigms indicated greater pain in PD patients, just failing to reach significance (SMD=0.30, p=0.06). These findings (a) support the existence of hyperalgesia in PD, which could contribute to the onset/intensity of clinical pain, and (b) implicate dopamine deficiency as a potential underlying mechanism, which may present opportunities for the development of novel analgesic strategies.
Topics: Dopamine; Humans; Hyperalgesia; Pain Perception; Parkinson Disease
PubMed: 28179128
DOI: 10.1016/j.arr.2017.01.005