Background and Aims: Current findings on altered evoked potentials (EPs) caused by morphine are based on common alterations for a group of subjects after drug administration. However, this ignores the analysis of individual responses, which may explain the clinical differences in efficacy. Therefore, we explored the individual responses to morphine in terms of the altered single-sweep characteristics in a placebo-controlled crossover study. To account for multifactorial mechanisms, several characteristics were assessed simultaneously by multivariate pattern analysis (MVPA). Methods: EPs were recorded from 62 channels and obtained before and after morphine and placebo administration during repeated electrical stimulations of the oesophagus in 12 healthy males. Additionally, the pain detection threshold was recorded to reflect the subjective analgesic effect in each subject. The characteristics of the sweeps were extracted by a multivariate matching pursuit algorithm with Gabor atoms implemented with a variable amplitude and constant phase across the sweeps. The single-sweep amplitudes were used as input to an MVPA algorithm to discriminate individual responses. The accuracy of the MVPA for each individual subject was used for correlation analysis of the analgesic effect. Results: The mean classification accuracy when discriminating pre- and posttreatment morphine responses was 72% (p = 0.01). The individual classification accuracy was positively correlated to the analgesic effect of morphine (p = 0.03). Furthermore, the 2 posttreatment responses were classified and validated by the classification of the 2 pretreatment responses (p = 0.001). Conclusions: The alterations in the single-sweep EPs after morphine reflect the analgesic effect. The MVPA approach is a novel methodology for monitoring the individual efficacy of analgesics.

Keywords:
Analgesics, Electroencephalography, Evoked brain potentials, Matching pursuit, Morphine, Multivariate pattern analysis, Opioids, Personalized medicine, Pharmaco-electroencephalography, Support vector machine
1.
Drewes AM, Gratkowski M, Sami SA, Dimcevski G, Funch-Jensen P, Arendt-Nielsen L: Is the pain in chronic pancreatitis of neuropathic origin? Support from EEG studies during experimental pain. World J Gastroenterol 2008;14:4020-4027.
2.
Frokjaer JB, Softeland E, Graversen C, Dimcevski G, Egsgaard LL, Arendt-Nielsen L, Drewes AM: Central processing of gut pain in diabetic patients with gastrointestinal symptoms. Diabetes Care 2009;32:1274-1277.
3.
Staahl C, Krarup AL, Olesen AE, Brock C, Graversen C, Drewes AM: Is electrical brain activity a reliable biomarker for opioid analgesia in the gut? Basic Clin Pharmacol Toxicol 2011;109:321-327.
4.
Quante M, Scharein E, Zimmermann R, Langer-Brauburger B, Bromm B: Dissociation of morphine analgesia and sedation evaluated by EEG measures in healthy volunteers. Arzneimittelforschung 2004;54:143-151.
5.
Lee MC, Mouraux A, Iannetti GD: Characterizing the cortical activity through which pain emerges from nociception. J Neurosci 2009;29:7909-7916.
6.
Peng YZ, Li XX, Wang YW: Effects of parecoxib and fentanyl on nociception-induced cortical activity. Mol Pain 2010;6:3.
7.
Riley J, Ross JR, Rutter D, Wells AU, Goller K, du Bois R, Welsh K: No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients. Support Care Cancer 2006;14:56-64.
8.
Bartnik EA, Blinowska KJ, Durka PJ: Single evoked potential reconstruction by means of wavelet transform. Biol Cybern 1992;67:175-181.
9.
Georgiadis SD, Ranta-aho PO, Tarvainen MP, Karjalainen PA: Single-trial dynamical estimation of event-related potentials: a Kalman filter-based approach. IEEE Trans Biomed Eng 2005;52:1397-1406.
10.
Jung TP, Makeig S, Westerfield M, Townsend J, Courchesne E, Sejnowski TJ: Analysis and visualization of single-trial event-related potentials. Hum Brain Mapp 2001;14:166-185.
11.
Truccolo WA, Ding M, Knuth KH, Nakamura R, Bressler SL: Trial-to-trial variability of cortical evoked responses: implications for the analysis of functional connectivity. Clin Neurophysiol 2002;113:206-226.
12.
Gasser T, Mocks J, Verleger R: Selavco: a method to deal with trial-to-trial variability of evoked potentials. Electroencephalogr Clin Neurophysiol 1983;55:717-723.
13.
Sieluzycki C, Konig R, Matysiak A, Kus R, Ircha D, Durka PJ: Single-trial evoked brain responses modeled by multivariate matching pursuit. IEEE Trans Biomed Eng 2009;56:74-82.
14.
Arvaneh M, Guan C, Ang KK, Quek C: Optimizing the channel selection and classification accuracy in EEG-based BCI. IEEE Trans Biomed Eng 2011;58:1865-1873.
15.
Sorensen TL, Olsen UL, Conradsen I, Henriksen J, Kjaer TW, Thomsen CE, Sorensen HB: Automatic epileptic seizure onset detection using matching pursuit: a case study. Conf Proc IEEE Eng Med Biol Soc 2010;2010:3277-3280.
16.
Oliveira PP Jr, Nitrini R, Busatto G, Buchpiguel C, Sato JR, Amaro E Jr: Use of SVM methods with surface-based cortical and volumetric subcortical measurements to detect Alzheimer's disease. J Alzheimers Dis 2010;19:1263-1272.
17.
Ban HJ, Heo JY, Oh KS, Park KJ: Identification of type 2 diabetes-associated combination of SNPs using support vector machine. BMC Genet 2010;11:26.
18.
Vapnik VN: An overview of statistical learning theory. IEEE Trans Neural Netw 1999;10:988-999.
19.
Lee Y: Support vector machines for classification: a statistical portrait. Methods Mol Biol 2010;620:347-368.
20.
Guideline 6: A proposal for standard montages to be used in clinical EEG. J Clin Neurophysiol 2006;23:111-117.
21.
Drewes AM, Arendt-Nielsen L, Jensen JH, Hansen JB, Krarup HB, Tage-Jensen U: Experimental pain in the stomach: a model based on electrical stimulation guided by gastroscopy. Gut 1997;41:753-757.
22.
Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L: Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus. Eur J Pain 2003;7:539-549.
23.
Graversen C, Brock C, Drewes AM, Farina D: Biomarkers for visceral hypersensitivity identified by classification of electroencephalographic frequency alterations. J Neural Eng 2011;8:056014.
24.
Gratkowski M, Haueisen J, Arendt-Nielsen L, Cn Chen A, Zanow F: Decomposition of biomedical signals in spatial and time-frequency modes. Methods Inf Med 2008;47:26-37.
25.
Blinowska KJ, Durka PJ, Zygierewicz J: Time-frequency analysis of brain electrical activity - adaptive approximations. Methods Inf Med 2004;43:70-73.
26.
Raehal KM, Bohn LM: Mu opioid receptor regulation and opiate responsiveness. AAPS J 2005;7:E587-E591.
27.
Durka PJ, Szelenberger W, Blinowska KJ, Androsiuk W, Myszka M: Adaptive time-frequency parametrization in pharmaco EEG. J Neurosci Methods 2002;117:65-71.
28.
Zhang Z, Luk KD, Hu Y: Identification of detailed time-frequency components in somatosensory evoked potentials. IEEE Trans Neural Syst Rehabil Eng 2010;18:245-254.
29.
Lelic D, Olesen SS, Valeriani M, Drewes AM: Brain source connectivity reveals the visceral pain network. Neuroimage 2012;60:37-46.
30.
Durka PJ, Matysiak A, Montes EM, Sosa PV, Blinowska KJ: Multichannel matching pursuit and EEG inverse solutions. J Neurosci Methods 2005;148:49-59.
31.
Durka PJ: From wavelets to adaptive approximations: time-frequency parametrization of EEG. Biomed Eng Online 2003;2:1.
32.
Jmail N, Gavaret M, Wendling F, Kachouri A, Hamadi G, Badier JM, Benar CG: A comparison of methods for separation of transient and oscillatory signals in EEG. J Neurosci Methods 2011;199:273-289.
33.
Lelic D, Gratkowski M, Hennings K, Drewes AM: Multichannel matching pursuit validation and clustering - a simulation and empirical study. J Neurosci Methods 2011;196:190-200.
34.
Lu Q, Jiang H, Luo G, Han Y, Yao Z: Multichannel matching pursuit of MEG signals for discriminative oscillation pattern detection in depression. Int J Psychophysiol 2013;88:206-212.
35.
Lu Q, Jiang H, Bi K, Liu C, Yao Z: Discriminative analysis with a limited number of MEG trials in depression. J Affect Disord 2014;167:207-214.
36.
Christensen JAE, Kempfner J, Zoetmulder M, Leonthin HL, Arvastson L, Christensen SR, Sørensen HBD, Jennum P: Decreased sleep spindle density in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease. Clin Neurophysiol 2014;125:512-519.
37.
Willoch F, Tolle TR, Wester HJ, Munz F, Petzold A, Schwaiger M, Conrad B, Bartenstein P: Central pain after pontine infarction is associated with changes in opioid receptor binding: a PET study with 11C-diprenorphine. AJNR Am J Neuroradiol 1999;20:686-690.
38.
Firestone LL, Gyulai F, Mintun M, Adler LJ, Urso K, Winter PM: Human brain activity response to fentanyl imaged by positron emission tomography. Anesth Analg 1996;82:1247-1251.
39.
Casey KL, Svensson P, Morrow TJ, Raz J, Jone C, Minoshima S: Selective opiate modulation of nociceptive processing in the human brain. J Neurophysiol 2000;84:525-533.
40.
Carlino E, Pollo A, Benedetti F: Placebo analgesia and beyond: a melting pot of concepts and ideas for neuroscience. Curr Opin Anaesthesiol 2011;24:540-544.
41.
Dowman R: Topographic analysis of painful laser and sural nerve electrical evoked potentials. Brain Topogr 2004;16:169-179.
42.
Chang PF, Arendt-Nielsen L, Graven-Nielsen T, Cn Chen A: Psychophysical and EEG responses to repeated experimental muscle pain in humans: pain intensity encodes EEG activity. Brain Res Bull 2003;59:533-543.
43.
Hobson AR, Sarkar S, Furlong PL, Thompson DG, Aziz Q: Identification of the optimal parameters for recording cortical potentials evoked by mechanical stimulation of the human oesophagus. Neurogastroenterol Motil 2000;12:163-171.
44.
Maier C, Hildebrandt J, Klinger R, Henrich-Eberl C, Lindena G: Morphine responsiveness, efficacy and tolerability in patients with chronic non-tumor associated pain - results of a double-blind placebo-controlled trial (Montas). Pain 2002;97:223-233.
45.
Riley J, Ross JR, Rutter D, Shah S, Gwilliam B, Wells AU, Welsh K: A retrospective study of the association between haematological and biochemical parameters and morphine intolerance in patients with cancer pain. Palliat Med 2004;18:19-24.
46.
D'Honneur G, Gilton A, Sandouk P, Scherrmann JM, Duvaldestin P: Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure. Anesthesiology 1994;81:87-93.
47.
Hasselstrom J, Eriksson S, Persson A, Rane A, Svensson JO, Sawe J: The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990;29:289-297.
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