Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-D-aspartate... Show moreImportance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-D-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes. Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions. What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief. Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR. Show less
Niesters, M.; Dahan, A.; Kest, B.; Zacny, J.; Stijnen, T.; Aarts, L.; Sarton, E. 2010
Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the... Show moreAlthough a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in mu and mixed mu/kappa opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on mu-opioids there was no significant sex-analgesia association. Restricting the analysis to patient-controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n = 15, effect size 0.22, 95% c.i. 0.02-0.42, P = 0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n = 11, effect size = 0.36, 95% c.i. 0.17-0.56, P = 0.003). Meta-regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on mu-opioids women had greater antinociception from opioids (n = 11, effect size = 0.35; 95% c.i. 0.01-0.69, P = 0.047), which was predominantly due to 6 morphine studies. Female patients had greater mu/kappa opioid analgesia (n = 7, effect size 0.84; 95% c.i. 0.25-1.43, P = 0.005), but no sex-analgesia association was present in experimental studies (n = 7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine mu and mixed mu/kappa-opioids are less convincing and require further study. (C) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Show less
Olofsen, E.; Mooren, R.; Dorp, E. van; Aarts, L.; Smith, T.; Hartigh, J. den; ... ; Sarton, E. 2010
BACKGROUND: In pharmacokinetic pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of... Show moreBACKGROUND: In pharmacokinetic pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of arteriovenous concentration differences of morphine-6-glucuronide (M6G) was quantified. We used simulation studies to estimate possible biases in pharmacodynamic model parameters when linking venous versus arterial concentrations to effect. METHODS: Seventeen healthy volunteers received an IV 90-second infusion of 0.3 mg/kg morphine-6-glucuronide (M6G). Arterial and venous blood samples, from the radial artery and cubital vein, respectively, were obtained. An extended pharmacokinetic model was constructed linking arterial and venous compartments. The extent of bias in pharmacodynamic model parameter estimates was explored in simulation studies with NONMEM, simulating M6G effect using first-order effect-compartment inhibitory sigmoid E-MAX models. M6G effect was simulated at various values for the arterial blood-effect-site equilibration half-lifes (t(1/2)k(EO)), ranging from 5 to 240 minutes. RESULTS: Arteriovenous concentration differences were apparent, with higher arterial plasma concentrations just after infusion, whereas at later times (>60 minutes) venous M6G concentrations exceeded arterial concentrations. The extended pharmacokinetic model adequately described the data and consisted of 3 arterial compartments, 1 central venous compartment, and 1 peripheral venous compartment. The simulation studies revealed large biases in model parameters derived from venous concentration data. The biases were dependent on the value of t(1/2)k(EO). Assuming that the true values of M6G t(1/2)k(EO) range from 120 to 240 minutes (depending on the end point measured), we would have underestimated t(1/2)k(EO) by 30%, whereas the potency parameter would have been overestimated by about 40%, when using venous plasma samples. CONCLUSIONS: Because of large arteriovenous differences in M6G plasma, concentration biases in pharmacodynamic model parameters will occur when linking venous concentration to effect, using a traditional effect-compartment model. (Anesth Analg 2010;111:626-32) Show less
Background: Few studies address the dynamic effect of opioids on respiration. Models with intact feedback control of carbon dioxide on ventilation (non-steady-state models) that correctly... Show moreBackground: Few studies address the dynamic effect of opioids on respiration. Models with intact feedback control of carbon dioxide on ventilation (non-steady-state models) that correctly incorporate the complex interaction among drug concentration, end-tidal partial pressure of carbon dioxide concentration, and ventilation yield reliable descriptions and predictions of the behavior of opioids. The authors measured the effect of remifentanil on respiration and developed a model of remifentanil-induced respiratory depression. Methods: Ten male healthy volunteers received remifentanil infusions with different infusion speeds (target concentrations: 4-9 ng/ml; at infusion rates: 0.17-9 ng . ml(-1) . min(-1)) while awake and at the background of low-dose propofol. The data were analyzed with a nonlinear model consisting of two additive linear parts, one describing the depressant effect of remifentanil and the other describing the stimulatory effect of carbon dioxide on ventilation. Results: The model adequately described the data including the occurrence of apnea. Most important model parameters were as follows: C-50 for respiratory depression 1.6 +/- 0.03 ng/ml, gain of the respiratory controller (G) 0.42 - 0.1 l.min(-1) . Torr(-1), and remifentanil blood effect site equilibration half-life (t1/2k(e0)) 0.53 +/- 0.2 min. Propofol caused a 20-50% reduction of C50 and G but had no effect on t1/2k(e0). Apnea occurred during propofol infusion only. A simulation study revealed an increase in apnea duration at infusion speeds of 2.5-0.5 ng.ml(-1).min(-1) followed by a reduction. At an infusion speed of <= 0.31 ng.ml(-1).min(-1), no apnea was seen. Conclusions: The effect of varying remifentanil infusions with and without a background of low-dose propofol on ventilation and end-tidal partial pressure of carbon dioxide concentration was described successfully using a non-steady-state model of the ventilatory control system. The model allows meaningful simulations and predictions. Show less
Olofsen, E.; Dorp, E. van; Teppema, L.; Aarts, L.; Smith, T.W.; Dahan, A.; Sarton, E. 2010
Background: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist ... Show moreBackground: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist -antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers. Methods: Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 = g naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 = g naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal PCO2. A mechanismbased pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data. Results: Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (k(off) M6G = 0.0327 +/- 0.00455 min(-1) versus morphine 0.138 +/- 0.0148 min(-1); values are typical +/- SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration. Conclusions: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration. Show less
Opioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opiod... Show moreOpioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opiod respiratory depression is by naloxone infusion. The efficacy of naloxone depends on its own pharmacological characteristics and on those (including receptor kinetics) of the opioid that needs reversal. Short elimination of naloxone and biophase equilibration half-lives and rapid receptor kinetics complicates reversal of high-affinity opioids. An opioid with high receptor affinity will require greater naloxone concentrations and/or a continuous infusion before reversal sets in compared with an opioid with lower receptor affinity. The clinical approach to severe opioid-induced respiratory depression is to titrate naloxone to effect and continue treatment by continuous infusion until chances for renarcotization have diminished. New approaches to prevent opioid respiratory depression without affecting analgesia have led to the experimental application of serotinine agonists, ampakines, and the antibiotic minocycline. Show less
