Katri Hamunen

Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety.

BACKGROUND:Gabapentin and pregabalin have antiallodynic and antihyperalgesic properties useful for treating neuropathic pain. These properties may also be beneficial in acute postoperative pain. In this study we evaluated randomized, controlled trials examining the analgesic efficacy, adverse effects, and clinical value of gabapentinoids in postoperative pain. METHODS:A systematic search of Medline, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) databases yielded 22 randomized, controlled trials on perioperative administration of gabapentinoids for postoperative pain relief. RESULTS:Pain relief was better in the gabapentin groups compared with the control groups. The opioid-sparing effect during the first 24 h after a single dose of gabapentin 300–1200 mg, administered 1–2 h preoperatively, ranged from 20% to 62%. The combined effect of a single dose of gabapentin was a reduction of opioid consumption equivalent to 30 ± 4 mg of morphine (mean ± 95% CI) during the first 24 h after surgery. Metaregression analysis suggested that the gabapentin-induced reduction in the 24-h opioid consumption was not significantly dependent on the gabapentin dose. Gabapentin reduced opioid-related adverse effects, such as nausea, vomiting, and urinary retention (number-needed-to-treat 25, 6, and 7, respectively). The most common adverse effects of the gabapentinoids were sedation and dizziness (number-needed-to-harm 35 and 12, respectively). CONCLUSIONS:Gabapentinoids effectively reduce postoperative pain, opioid consumption, and opioid-related adverse effects after surgery. Conclusions about the optimal dose and duration of the treatment cannot be made because of the heterogeneity of the trials. Studies are needed to determine the long-term benefits, if any, of perioperative gabapentinoids.

Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews.

BACKGROUNDnAntiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled Anticonvulsants for acute and chronic pain. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009.nnnOBJECTIVESnTo provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use.nnnMETHODSnWe included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data.We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation.nnnMAIN RESULTSnNo studies reported top tier results.For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more.For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias.Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine.nnnAUTHORS CONCLUSIONSnClinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin.There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.

Estimate at your peril: imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses.

a Pain Research and Nuffield Division of Anaesthetics, Department of Clinical Neurosciences, University of Oxford, The Churchill Hospital, Oxford, UK b Department of Occupational, Social and Environmental Medicine, University Medical Center Göttingen, Göttingen, Germany c Centre for Pain Research, The University of Bath, Bath, UK d The UK Cochrane Centre, NHS R&D Programme, Summertown Pavilion, Middle Way, Oxford, UK e Pain Clinic/Regional Centre of Excellence in Palliative Care, Haukeland University Hospital, Bergen, Norway f Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Meilahti Hospital, Helsinki, Finland g College of Human and Health Sciences, Swansea University, Swansea, Wales, UK

Trends in opioid consumption in the Nordic countries 2002-2006.

Objective: The purpose of the study was to examine the trends in opioid consumption in the five Nordic countries between 2002 and 2006 and to explore possible explanations for changes in the quality and quantity of opioids consumed.

What do different databases tell about the use of opioids in seven European countries in 2002

Objective: The objective of this paper was to analyse opioid consumption in a number European countries using different sources of data.

Systematic review on analgesics given for pain following tonsillectomy in children.

&NA; In this systematic review effectiveness of analgesics for pain after tonsillectomy in children was evaluated and trial methodology of the included studies explored. Databases were searched for randomised, controlled studies on systemic paracetamol, NSAIDs and opioids. Eighty‐four studies were evaluated for inclusion. Thirty‐six studies were included and 48 excluded. Only in two studies investigated analgesics were given postoperatively for pain. All other studies investigated prophylactic administration of analgesics. Only five studies were truly placebo controlled. Trial methodology of the included studies varied greatly in respect to analgesics and doses used, duration of follow‐up periods, methods of pain measurement, rescue analgesics and criteria for administrating rescue analgesia used. Sensitivity of studies was often unclear. Only 16 out of 36 studies were considered to be sensitive. Because of highly variable methodology and lack of sensitivity only limited conclusions on clinical efficacy of analgesics investigated can be drawn. No analgesic in single prophylactic dose provided analgesia for day of operation. Further studies are needed to find the optimal analgesic(s) for pain after tonsillectomy in children.

The effect of erythromycin and fluvoxamine on the pharmacokinetics of intravenous lidocaine.

Inhibitors of CYP3A4 (cytochrome P450 3A4) have a minor effect on lidocaine pharmacokinetics. We studied the effect of coadministration of the antidepressant fluvoxamine (CYP1A2 inhibitor) and antimicrobial drug erythromycin (CYP3A4 inhibitor) on lidocaine pharmacokinetics in a double-blind, randomized, three-way crossover study. Nine volunteers ingested daily 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos for 5 days. On day 6, 1.5 mg/kg lidocaine was administered IV over 60 min. Concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured for 10 h. Fluvoxamine alone decreased the clearance of lidocaine by 41% (P < 0.001) and prolonged its elimination half-life from 2.6 to 3.5 h (P < 0.01). During the combination of fluvoxamine and erythromycin, lidocaine clearance was 53% smaller than during placebo (P < 0.001) and 21% smaller than during fluvoxamine alone (P < 0.05). During the combination phase the half-life of lidocaine (4.3 h) was longer than during the placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity. Concomitant use of both fluvoxamine and a CYP3A4 inhibitor such as erythromycin can further increase plasma lidocaine concentrations by decreasing its clearance.

The effect of paracetamol and tropisetron on pain: experimental studies and a review of published data.

Experimental studies suggest that paracetamol‐induced analgesia is mediated via central serotonergic pathways and attenuated by 5‐HT3‐antagonists. However, clinical studies do not support this, and 5‐HT3‐antagonists are expected to reduce pain by blocking the descending pronociceptive pathway. The current project tested whether tropisetron attenuates analgesia by paracetamol. Two randomized, double‐blind, crossover studies with 18 healthy male volunteers in each were performed. Pain stimuli were cold water immersion (cold pressor test), contact heat pain (study 1) and electrical stimulation (study 2). In both studies, tropisetron 5 mg i.v. or saline was administered, followed by paracetamol 2 g i.v. 30 min. later. Individual changes in heat and cold pain intensity, cold pain tolerance and unpleasantness were recorded. The same thresholds were also expressed as scores (% of the individual score at baseline). Additionally, previously published findings on the effects of paracetamol and its interaction with 5HT3‐antagonists in human experimental pain models were reviewed. After calculation of the sensory and pain scores (%), tropisetron seemed to amplify the analgesic action of paracetamol. Paracetamol 2 g i.v. did not show any statistically significant analgesia in thermal tests (study 1), or differences in sensory, pain detection or moderate pain thresholds of the electrical stimulus (study 2). As paracetamol did not have a measurable analgesic effect in these tests, no conclusions can be drawn about the interaction between paracetamol and tropisetron. However, tropisetron may have an analgesic effect of its own. Clinicians should not avoid using these drugs together, unless larger clinical studies indicate otherwise.

A systematic review of trial methodology, using the placebo groups of randomized controlled trials in paediatric postoperative pain.

&NA; Trial methodology was evaluated in paediatric analgesic studies. Databases were searched for randomised, placebo controlled studies of systemic paracetamol, NSAIDs and opioids administered for acute postoperative pain in children. Eighty‐three studies met the inclusion criteria and 40 were included for the analysis. Analgesics were administered for established postoperative pain in two studies only. In all other studies they were administered in a prophylactic manner. As study design and sensitivity are particularly demanding in studies using pre‐emptive dosing of analgesics, the placebo groups were analysed for issues of study sensitivity. Postoperative pain outcomes included pain scores in 34, rescue analgesia in 36, time to first rescue analgesia in 15, pain on activity in eight, number of patients with pain in six, pain relief in three, global efficacy rating in two and analgesic consumption via PCA in four studies. Twenty of 36 studies reported criteria for rescue analgesia that varied from 20 to 77% of the maximum pain intensity. Need of rescue analgesia showed more often differences between study groups than time to first rescue analgesia or pain intensity. Rescue analgesia was administered to 21–100% of the patients in the placebo groups where no other analgesics were given perioperatively. Most patients in the placebo groups had pain that was greater than 30% of the maximum. In conclusion, analysis of the methodology showed several aspects of trial design that can be improved in future studies. Placebo control groups can be used in paediatric analgesic studies to demonstrate internal sensitivity.

Interpretation of the large red-and-white visual analog scale by children compared with adults.

The red-and-white visual analog scale (VAS) is a modification of the traditional VAS. The purpose of this study was to compare how children of various ages and adults rate their anticipatory pain intensity on the red-and-white VAS. One hundred children were interviewed as part of the anesthesiologists preoperative visit before elective eye surgery. For comparison, 50 healthy adults were interviewed in a similar manner. The medians and ranges describing mild, moderate, and severe pain, or pain intensity at which medicine would be requested, did not differ between preschool children, young schoolchildren, and adolescents or between children and adults. The median score of anticipated need for pain medication was 50% of the maximum for children.