It is not straightforward to simultaneously evaluate the beneficial and harmful effects of pain management, since different drugs may possess different analgesia and adverse effect profiles.... Show moreIt is not straightforward to simultaneously evaluate the beneficial and harmful effects of pain management, since different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here, we construct "pragmatic" utility functions based on measurements of benefit and harm, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics. Using data from two previous studies, utility functions were designed by estimating the probability of occurrence of benefit and harm and combining these into one function. Study 1 was a clinical trial on the effect of oral pregabalin on pain relief in chronic pancreatitis patients, with endpoint analgesia and dizziness monitored for 21 days. Study 2 was an experimental study on the effect of intravenous fentanyl on antinociception and respiratory depression in healthy volunteers. From study 1, the utility function was negative the first week of treatment, indicative of the greater probability of dizziness than analgesia, but positive thereafter. From study 2, the utility function showed a nadir 30 minutes after dosing, after which the probability function slowly increased toward zero. A pragmatic utility function based on the probability of two binary outcomes, analgesia and adverse effect, was successfully constructed using data from the two previous studies. The results yielded valuable insights into the utility of treatment and may be highly educative for physicians and potentially used in development of potent analgesics without serious side effects. Show less
Donk, T. van de; Velzen, M. van; Dahan, A.; Niesters, M. 2019
IMPORTANCE An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that... Show moreIMPORTANCE An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted.OBJECTIVES To determine the prevalence of opioid prescriptions and adverse events associated with opioids, and to identify risk factors associated with opioid prescription in the Dutch population.DESIGN, SETTING, AND PARTICIPANTS This cohort study used national statistics from the Netherlands from January 1, 2013, to December 31, 2017, including the full Dutch population of 16 779 575 people in 2013 and 17 081507 people in 2017. Data from the Dutch Health Monitor surveys of 2012 and 2016 were also included. Databases were anonymized prior to analysis. All analyses were performed between December 2018 and February 2019.EXPOSURE Opioid prescription.MAIN OUTCOMES AND MEASURES The main outcomes were the dynamics of opioid prescriptions, hospital admissions for opioid overdose, and opioid overdose mortalities. The secondary outcome was risk factors associated with opioid prescription.RESULTS In 2013, 814 211 individuals (4.9% of the total population) received an opioid prescription. In 2017, 1027 019 individuals (6.0% of the total population) received at least 1 opioid prescription (mean [SD] age, 59.3 [18.5] years; 613 203 [59.7%] women). The rate of hospital admissions for opioid overdose was 9.2 per 100 000 inhabitants in 2013 and 13.1 per 100 000 inhabitants in 2017 (relative risk, 1.43 [95% CI, 1.34-1.52]). Similarly, an increased risk of opioid overdose death was observed, from 0.83 per 100 000 inhabitants in 2013 to 1.2 per 100 000 inhabitants in 2017 (relative risk, 1.49 [95% CI, 1.20-1.85]). Based on data from the 2012 Dutch Health Monitor survey, risk factors associated with opioid prescription included being older than 65 years (odds ratio [OR], 4.20 [95% CI, 3.98-4.43]), having only a primary school education (OR, 3.62 [95% CI, 3.46-3.77]), being widowed (OR, 3.30 [95% CI, 3.13-3.49]), reporting always feeling symptoms of depression (OR, 3.77 [95% CI, 3.41-4.18]), and reporting poor or very poor physical health (OR, 10.40 [95% CI, 10.01-10.81]). Self-reported back pain (OR, 4.34 [95% CI, 4.23-4.46]) and rheumatoid arthritis or fibromyalgia (OR, 3.77 [95% CI, 3.65-3.90]) were also associated with opioid prescription. However, unemployment (OR, 1.05 [95% CI, 0.96-1.13]) was not associated with opioid prescription, and alcohol use disorder (OR, 0.76 [95% CI, 0.73-0.80]) was negatively associated with opioid prescription.CONCLUSIONS AND RELEVANCE This study found that opioid prescriptions have increased in the Netherlands. Although the risk of adverse events is still relatively low, there is an urgent need to review pain management to prevent a further increase in opioid prescription. Show less
In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in twenty chronic pain patients with... Show moreIn this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in twenty chronic pain patients with fibromyalgia. We tested four different cannabis varieties with exact knowledge on their ∆9-tetrahydrocannabinol (THC), and cannabidiol (CBD) content: Bedrocan® (22.4 mg THC, < 1 mg CBD), Bediol® (13.4 mg THC, 17.8 mg CBD), Bedrolite® (18.4 mg CBD, < 1 mg THC) and a placebo variety without any THC or CBD. Following a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol® displayed a 30% decrease in pain scores compared to placebo (90% vs. 55% of patients, p = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (r = -0.5, p < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (p < 0.01). CBD inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of a synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC-CBD interactions and the role of psychotropic symptoms on pain relief. Show less
Hoogd, S. de; Valkenburg, A.J.; Dongen, E.P.A. van; Daeter, E.J.; Rosmalen, J. van; Dahan, A.; ... ; Knibbe, C.A.J. 2019
Earlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that... Show moreEarlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that remifentanil plays a minor role in the development of chronic thoracic pain. Still, the relatively high incidence of chronic thoracic pain and its accompanying impact on quality of life remain challenging problems.\nBoth warm and cold detection, and pain thresholds, were not significantly different between the remifentanil and fentanyl groups 3 days and 12 months after surgery (P > 0.05). No significant predictors for altered pain sensitivity were identified.\nThe study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02031016).\nThe clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term.\nThe current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing.\nA single-blind, randomised controlled trial.\nA tertiary care teaching hospital in The Netherlands, from 2014 to 2016.\nA total of 126 patients aged between 18 and 85 years, undergoing cardiothoracic surgery via sternotomy (coronary artery bypass grafts and/or valve replacement) were included. Exclusion criteria were BMI above 35 kg m, history of cardiac surgery, chronic pain conditions, neurological conditions, allergy to opioids or paracetamol, language barrier and pregnancy.\nPatients were allocated randomly to receive intra-operatively either a continuous remifentanil infusion or intermittent intra-operative fentanyl as needed in addition to standardised anaesthesia with propofol and intermittent intravenous fentanyl at predetermined time points.\nWarm and cold detection and pain thresholds 3 days and 12 months after surgery. In addition the use of remifentanil, presence of postoperative chronic pain, age, opioid consumption and pre-operative quality of life were tested as a predictor for altered pain sensitivity 12 months after surgery.\nCONCLUSION\nRESULTS\nTRIAL REGISTRATION\nBACKGROUND\nOBJECTIVE\nDESIGN\nSETTING\nPATIENTS\nINTERVENTIONS\nMAIN OUTCOME MEASURES Show less
Donk, T. van de; Velzen, M. van; Dahan, A.; Niesters, M. 2019
Background: Tapentadol is a centrally acting analgesic with μ-agonistic activity combined with noradrenaline reuptake inhibition. Its mechanism of action relies on improvement of descending pain... Show moreBackground: Tapentadol is a centrally acting analgesic with μ-agonistic activity combined with noradrenaline reuptake inhibition. Its mechanism of action relies on improvement of descending pain inhibition. In the current study, tapentadol’s ability to enhance conditioned pain modulation (CPM, an experimental measure of descending pain inhibition) was evaluated in fibromyalgia patients with absent or reduced CPM responses.Methods: A total of 34 fibromyalgia patients completed this double-blind trial. Patients were randomized to receive treatment with tapentadol sustained-release or placebo for a 3-month period with 1-month follow-up. At baseline the cornea nerve fiber state (CNFS) was quantified to determine the presence of nerve fiber pathology and assess its value in the prediction of the analgesic response.Results: Tapentadol significantly increased CPM responses during treatment with an average increase from baseline of 20.5 ± 12.5% (tapentadol) versus 3.0 ± 11.2% (placebo; p = 0.042). No treatment effect was observed for the absolute pain scores, however analgesia responder rate analyses demonstrated a treatment effect in favor of tapentadol. Pain relief (a reduction in pain score ³ 30%) was predicted by the presence of a normal CNFS (p = 0.035). Patients with an abnormal CNFS had no analgesic effect from tapentadol despite an increase in CPM.Conclusions: In chronic pain patients with fibromyalgia, the increase in endogenous pain inhibition by tapentadol was translated into analgesia in patients with a normal CNFS. In those with abnormal CNFS, tapentadol treatment was without analgesic effect. Show less
Meijer, F.S.; Martini, C.H.; Broens, S.; Boon, M.; Niesters, M.; Aarts, L.; ... ; Dahan, A. 2019
What We Already Know about This Topic: The nociception level index (Medasense Biometrics Ltd., Ramat Gan, Israel), is a reliable measure of moderate to intense noxious stimulation during anesthesia... Show moreWhat We Already Know about This Topic: The nociception level index (Medasense Biometrics Ltd., Ramat Gan, Israel), is a reliable measure of moderate to intense noxious stimulation during anesthesia and surgery What This Article Tells Us That Is New: In a randomized trial in patients having major abdominal surgery, compared to standard practice, nociception level-guided analgesia resulted in 30% less intraoperative remifentanil consumption Background: The multidimensional index of nociception, the nociception level, outperforms blood pressure and heart rate in detection of nociceptive events during anesthesia. We hypothesized that nociception level–guided analgesia reduces opioid consumption and suboptimal anesthesia events such as low blood pressure and use of vasoactive medication. Methods: In this single-blinded randomized study, 80 American Society of Anesthesiologists class I–III adult patients of either sex, scheduled for major abdominal procedures under remifentanil/propofol anesthesia by target-controlled infusion, were included. During the procedure nociception level, noninvasive blood pressure, and heart rate were monitored. Patients were randomized to receive standard clinical care or nociception level–guided analgesia. In the nociception level–guided group, remifentanil concentration was reduced when index values were less than 10 or increased when values were above 25 for at least 1 min, in steps of 0.5 to 1.0 ng/ml. Propofol was titrated to bispectral index values between 45 and 55. The primary outcomes of the study were remifentanil and propofol consumption and inadequate anesthesia events. Results: Compared with standard care, remifentanil administration was reduced in nociception level–guided patients from (mean ± SD) 0.119 ± 0.033 to 0.086 ± 0.032 μg · kg-1 · min-1 (mean difference, 0.039 μg · kg-1 · min-1; 95% CI, 0.025–0.052 μg · kg-1 · min-1; P < 0.001). Among nociception level–guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (relative risk, 0.271; 95% CI, 0.08–0.77; P = 0.006). In the nociception level–guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (relative risk, 0.64; 95% CI, 0.40–0.99; P = 0.044). Conclusions: Nociception level-guided analgesia during major abdominal surgery resulted in 30% less remifentanil consumption. Show less
Broens, S.J.L.; Boon, M.; Martini, C.H.; Niesters, M.; Velzen, M. van; Aarts, L.P.H.J.; Dahan, A. 2019
Background: The ventilatory response to hypoxia is a life-saving chemoreflex originating at the carotid bodies that is impaired by nondepolarizing neuromuscular blocking agents. This study... Show moreBackground: The ventilatory response to hypoxia is a life-saving chemoreflex originating at the carotid bodies that is impaired by nondepolarizing neuromuscular blocking agents. This study evaluated the effect of three strategies for reversal of a partial neuromuscular block on ventilatory control in 34 healthy male volunteers on the chemoreflex. The hypothesis was that the hypoxic ventilatory response is fully restored following the return to a trainof- four ratio of 1. Methods: In this single-center, experimental, randomized, controlled trial, ventilatory responses to 5-min hypoxia (oxygen saturation, 80 ± 2%) and ventilation at hyperoxic isohypercapnia (end-tidal carbon dioxide concentration, 55 mmHg) were obtained at baseline, during rocuronium-induced partial neuromuscular block (train-of-four ratio of 0.7 measured at the adductor pollicis muscle by electromyography), and following reversal until the train-of-four ratio reached unity with placebo (n = 12), 1 mg neostigmine/0.5 mg atropine (n = 11), or 2 mg/kg sugammadex (n = 11). Results: This study confirmed that low-dose rocuronium reduced the ventilatory response to hypoxia from 0.55 ± 0.22 (baseline) to 0.31 ± 0.21 l · min−1 · %−1 (train-of-four ratio, 0.7; P < 0.001). Following full reversal as measured at the thumb, there was persistent residual blunting of the hypoxic ventilatory response (0.45 ± 0.16 l · min−1 · %−1; train-of-four ratio, 1.0; P < 0.001). Treatment effect was not significant (analysis of covariance, P = 0.299) with chemoreflex impairment in 5 (45%) subjects following sugammadex reversal, in 7 subjects (64%) following neostigmine reversal, and in 10 subjects (83%) after spontaneous reversal to a train-of-four ratio of 1. Conclusions: Despite full reversal of partial neuromuscular block at the thumb, impairment of the peripheral chemoreflex may persist at train-of-four ratios greater than 0.9 following reversal with neostigmine and sugammadex or spontaneous recovery of the neuromuscular block. Show less
