Carina Graversen

Quantitative Sensory Testing Predicts Pregabalin Efficacy in Painful Chronic Pancreatitis

Background A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. Methods Sixty-four patients with painful chronic pancreatitis received pregabalin (150–300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. Results The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9–1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5–2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. Conclusions The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient’s individual sensory profile and thus comprises a significant step towards personalized pain medicine.

The analgesic effect of pregabalin in patients with chronic pain is reflected by changes in pharmaco-EEG spectral indices

AIM To identify electroencephalographic (EEG) biomarkers for the analgesic effect of pregabalin in patients with chronic visceral pain. METHODS This was a double-blind, placebo-controlled study in 31 patients suffering from visceral pain due to chronic pancreatitis. Patients received increasing doses of pregabalin (75mg-300mg twice a day) or matching placebo during 3 weeks of treatment. Pain scores were documented in a diary based on a visual analogue scale. In addition, brief pain inventory-short form (BPI) and quality of life questionnaires were collected prior to and after the study period. Multi-channel resting EEG was recorded before treatment onset and at the end of the study. Changes in EEG spectral indices were extracted, and individual changes were classified by a support vector machine (SVM) to discriminate the pregabalin and placebo responses. Changes in individual spectral indices and pain scores were correlated. RESULTS Pregabalin increased normalized intensity in low spectral indices, most prominent in the theta band (3.5-7.5Hz), difference of -3.18, 95% CI -3.57, -2.80; P= 0.03. No changes in spectral indices were seen for placebo. The maximum difference between pregabalin and placebo treated patients was seen in the parietal region, with a classification accuracy of 85.7% (P= 0.009). Individual changes in EEG indices were correlated with changes in pain diary (P= 0.04) and BPI pain composite scores (P= 0.02). CONCLUSIONS Changes in spectral indices caused by slowing of brain oscillations were identified as a biomarker for the central analgesic effect of pregabalin. The developed methodology may provide perspectives to assess individual responses to treatment in personalized medicine.

Randomised clinical trial: pregabalin attenuates experimental visceral pain through sub-cortical mechanisms in patients with painful chronic pancreatitis

Aliment Pharmacol Ther 2011; 34: 878–887

Slowed EEG rhythmicity in patients with chronic pancreatitis: evidence of abnormal cerebral pain processing?

Background and aim Intractable pain usually dominates the clinical presentation of chronic pancreatitis (CP). Slowing of electroencephalogram (EEG) rhythmicity has been associated with abnormal cortical pain processing in other chronic pain disorders. The aim of this study was to investigate the spectral distribution of EEG rhythmicity in patients with CP. Patients and methods Thirty-one patients with painful CP (mean age 52 years, 19 male) and 15 healthy volunteers (mean age 49, nine male) were included. A multichannel EEG was recorded from 62 surface electrodes. Amplitude strengths of the resting EEG were retrieved based on wavelet frequency analysis and summarized in frequency bands with corresponding topographic mapping. Results Patients with CP had slowed EEG rhythmicity compared with healthy volunteers. This was evident as increased activity in the lower frequency bands &dgr; (1–3.5 Hz) (P=0.05), &thgr; (3.5–7.5 Hz) (P<0.001) and &agr; (7.5–13.5 Hz) (P<0.001). Due to normalization a reciprocal relationship was observed for the high frequency band &bgr; (13.5–32 Hz). In a sub-analysis, &dgr; band activity was modified by diabetes, opioid treatment and alcohol aetiology of CP. However, no effect modification was seen for the &thgr; or &agr; bands. Differences in &thgr; activity were located over centro-frontal brain regions, whereas differences in &dgr;, &agr; and &bgr; band activity were located in frontal regions. Conclusion Slowed EEG rhythmicity was evident in patients with CP. This possibly mirrors abnormal central pain processing and may serve as a clinically useful biomarker of abnormal central pain processing.

Gastrointestinal symptoms in type-1 diabetes: Is it all about brain plasticity?

BACKGROUND AND AIMS Autonomic neuropathy seems to play a central role in the development of gastrointestinal symptoms in diabetes. In order to explore the neuronal mechanisms behind the symptoms we evaluated the brain processing of painful visceral stimuli. METHODS Evoked brain potentials were recorded to assess the response to painful oesophageal electrical stimuli in 15 healthy volunteers and 14 type-1 diabetes patients with autonomic neuropathy and related gastrointestinal symptoms. Source reconstruction analysis (fixed Multiple Signal Classification (MUSIC) algorithm) was applied to estimate the location of the evoked electrical activity in the brain. RESULTS The patients had increased oesophageal sensory thresholds compared to the controls (P=0.004). The latencies of the evoked brain potentials at vertex (Cz) were increased (P=0.007) and amplitudes reduced (P=0.011) in diabetics. Compared with controls the patients had a posterior shift of the electrical sources in the anterior cingulate cortex at 54 ms, and additional sources close to the posterior insula at 95 ms and in medial frontal gyrus at 184 ms. CONCLUSIONS There is evidence of altered central processing to visceral stimulation, and both peripheral and central mechanisms seem involved. Central neuronal reorganisation may contribute to our understanding of the gastrointestinal symptoms in patients with diabetic autonomic neuropathy and this may guide development and evaluation of new treatment modalities.Background and aims: Autonomic neuropathy seems to play a central role in the development of gastrointestinal symptoms in diabetes. In order to explore the neuronal mechanisms behind the symptoms we evaluated the brain processing of painful visceral stimuli.

Electroencephalography and analgesics

To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy. We searched PubMed with MeSH terms ‘analgesics’, ‘electroencephalography’ and ‘evoked potentials’ for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified. Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N‐methyl‐D‐aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed. This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients.

Central processing of gut pain in diabetic patients with gastrointestinal symptoms.

OBJECTIVE To evaluate the brains responses to painful visceral and somatic stimuli in diabetic patients with gastrointestinal symptoms. RESEARCH DESIGN AND METHODS The sensitivity to electrical esophageal and median nerve stimulations was assessed in 15 healthy volunteers and 14 type 1 diabetic patients with autonomic neuropathy and gastrointestinal symptoms using a euglycemic-hyperinsulinemic clamp. Evoked brain potentials were recorded. RESULTS Patients had reduced sensitivity to esophageal (48%; P < 0.001) and median nerve (80%; P < 0.001) stimulations. They also had increased (8.8%; P = 0.007) and nonreproducible (P = 0.006) latencies of evoked potentials in response to esophageal stimulations, with 26% reduction in amplitude (P = 0.011). No potential differences were seen to median nerve stimulations. In diabetic patients, the topographic location of the first peak in potentials was more central (P < 0.001) and gastrointestinal symptoms correlated with characteristics of brain potentials (P = 0.049). CONCLUSIONS This study supports that diabetes induces changes in peripheral visceral nerves as well as in the central nervous system.

Pharmacological pain management in chronic pancreatitis

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge. Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders. An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established, the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive. Consequently, the management of pain by traditional methods based on nociceptive deafferentation (e.g., surgery and visceral nerve blockade) becomes difficult and often ineffective. This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis. Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source, which should be reserved for special and carefully selected cases. In this review, we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis. In addition, future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.

Peripheral and central nervous contribution to gastrointestinal symptoms in diabetic patients with autonomic neuropathy.

Long‐term diabetes mellitus (DM) has been associated with neuronal changes in the enteric, peripheral and/or central nervous system. Moreover, abnormal visceral sensation and gastrointestinal (GI) symptoms are seen in up to 75% of patients. To explore the role of diabetic autonomic neuropathy (DAN) in patients with long‐standing DM, we investigated psychophysical responses and neuronal activity recorded as evoked brain potentials and dipolar source modelling.

Dynamic spectral indices of the electroencephalogram provide new insights into tonic pain.

OBJECTIVE This study aimed to investigate reliability of electroencephalography (EEG) during rest and tonic pain. Furthermore, changes in EEG between the two states as well as dynamics and relation to pain ratings were investigated. METHODS On two separate days EEG was recorded in 39 subjects during rest and tonic pain (cold pressor test: left hand held in 2°C water for 2 min.) while pain intensity was rated continuously. Dynamic spectral analysis was performed on the EEG. Between-day reliability of spectral indices was assessed and correlations to pain ratings were investigated. RESULTS EEG reliability was high during both states. The relative spectral indices increased in delta (1-4 Hz; P=0.0002), beta3 (18-32 Hz; P<0.0001) and gamma (32-70 Hz; P<0.0001) bands during tonic pain, and decreased in theta (4-8 Hz; P<0.0001), alpha1 (8-10 Hz; P<0.0001), alpha2 (10-12 Hz; P<0.0001) bands. Theta, beta3 and gamma bands correlated significantly to the area-under-curve of pain ratings, but only theta was dynamic and correlated to the pain ratings (R=0.88, P<0.0001). CONCLUSIONS EEG assessed during tonic pain is a valid experimental pain model both in terms of reliability between days and in connection between cortical activity and pain perception. SIGNIFICANCE EEG during tonic pain is more pain-specific and should be used in future basic and pharmacological studies.