Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial.

Opioids change gut motility, and opium tincture has been used for treatment of chronic diarrhoea for centuries. However, the effects have never been documented in controlled trials. We aimed to investigate the effects of opium tincture on gastrointestinal transit and motility, frequency of bowel movements, stool consistency, gastrointestinal symptoms and sedation. Twenty healthy subjects were included in this randomized controlled trial. Opium tincture or placebo was each applied for 9 days. Gastrointestinal transit and motility were investigated with the 3D-transit system. Bowel movements and gastrointestinal symptoms were recorded daily. General cognition, reaction time, memory and electroencephalography were used to assess effects on the central nervous system. Opium tincture doubled colonic transit (49 vs. 23 h, p < 0.001), decreased antegrade colonic movements (p < 0.05), reduced daily bowel movements (0.7 vs. 1.2, p < 0.001) and increased stool consistency (Type 3 vs. Type 4, p < 0.001). No changes in general cognition, reaction time or memory were observed, and minor changes of power observed by electroencephalography did not indicate sedation. This study is the first to show that opium tincture has anti-propulsive properties in the healthy gut, while no sedative effects were seen. This indicates that opium tincture is a relevant and safe treatment option in chronic diarrhoea.

Cervical transcutaneous vagal neuromodulation in chronic pancreatitis patients with chronic pain: A randomised sham controlled clinical trial.

BACKGROUND & AIMS: Chronic abdominal pain is the primary symptom of chronic pancreatitis, but unfortunately it is difficult to treat. Vagal nerve stimulation studies have provided evidence of anti-nociceptive effect in several chronic pain conditions. We investigated the pain-relieving effects of transcutaneous vagal nerve stimulation in comparison to sham treatment in chronic pancreatitis patients. METHODS: We conducted a randomised double-blinded, sham-controlled, crossover trial in patients with chronic pancreatitis. Patients were randomly assigned to receive a two-week period of cervical transcutaneous vagal nerve stimulation using the gammaCore device followed by a two-week sham stimulation, or vice versa. We measured clinical and experimental endpoints before and after each treatment. The primary clinical endpoint was pain relief, documented in a pain diary using a visual analogue scale. Secondary clinical endpoints included Patients' Global Impression of Change score, quality of life and Brief Pain Inventory questionnaire. Secondary experimental endpoints included cardiac vagal tone and heart rate. RESULTS: No differences in pain scores were seen in response to two weeks transcutaneous vagal nerve stimulation as compared to sham treatment (difference in average pain score (visual analogue scale): 0.17, 95%CI (-0.86;1.20), P = 0.7). Similarly, no differences were seen for secondary clinical endpoints, except from an increase in the appetite loss score (13.9, 95%CI (0.5:27.3), P = 0.04). However, improvements in maximum pain scores were seen for transcutaneous vagal nerve stimulation and sham treatments as compared to their respective baselines: vagal nerve stimulation (-1.3±1.7, 95%CI (-2.21:-0.42), P = 0.007), sham (-1.3±1.9, 95%CI (-2.28:-0.25), P = 0.018). Finally, heart rate was decreased after two weeks transcutaneous vagal nerve stimulation in comparison to sham treatment (-3.7 beats/min, 95%CI (-6.7:-0.6), P = 0.02). CONCLUSION: In this sham-controlled crossover study, we found no evidence that two weeks transcutaneous vagal nerve stimulation induces pain relief in patients with chronic pancreatitis. TRIAL REGISTRATION NUMBER: The study is registered at NCT03357029; www.clinicaltrials.gov.

Chiropractic Spinal Adjustment Increases the Cortical Drive to the Lower Limb Muscle in Chronic Stroke Patients.

This study aimed to investigate the effects of a single session of chiropractic spinal adjustment on the cortical drive to the lower limb in chronic stroke patients. In a single-blinded, randomized controlled parallel design study, 29 individuals with chronic stroke and motor weakness in a lower limb were randomly divided to receive either chiropractic spinal adjustment or a passive movement control intervention. Before and immediately after the intervention, transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) were recorded from the tibialis anterior (TA) muscle of the lower limb with the greatest degree of motor weakness. Differences in the averaged peak-peak MEP amplitude following interventions were calculated using a linear regression model. Chiropractic spinal adjustment elicited significantly larger MEP amplitude (pre = 0.24 ± 0.17 mV, post = 0.39 ± 0.23 mV, absolute difference = +0.15 mV, relative difference = +92%, p < 0.001) compared to the control intervention (pre = 0.15 ± 0.09 mV, post = 0.16 ± 0.09 mV). The results indicate that chiropractic spinal adjustment increases the corticomotor excitability of ankle dorsiflexor muscles in people with chronic stroke. Further research is required to investigate whether chiropractic spinal adjustment increases dorsiflexor muscle strength and walking function in people with stroke.

Investigating the Effects of Chiropractic Spinal Manipulation on EEG in Stroke Patients.

: Objective: The purpose of this study was to evaluate the impact of chiropractic spinal manipulation on the early somatosensory evoked potentials (SEPs) and resting-state electroencephalography (EEG) recorded from chronic stroke patients. Methods: Seventeen male patients (53 ± 12 years old) participated in this randomized cross-over study. The patients received chiropractic spinal manipulation and control intervention, in random order, separated by at least 24 hours. EEG was recorded before and after each intervention during rest and stimulation of the non-paretic median nerve. For resting-state EEG, the delta-alpha ratio, brain-symmetry index, and power-spectra were calculated. For SEPs, the amplitudes and latencies of N20 and N30 peaks were assessed. Source localization was performed on the power-spectra of resting-state EEG and the N30 SEP peak. Results: Following spinal manipulation, the N30 amplitude increased by 39%, which was a significant increase compared to the control intervention (p < 0.01). The latency and changes to the strength of the cortical sources underlying the N30 peak were not significant. The N20 peak, the resting-state power-spectra, delta-alpha ratio, brain-symmetry index, and resting-state source localization showed no significant changes after either intervention. Conclusion: A single session of chiropractic spinal manipulation increased the amplitude of the N30 SEP peak in a group of chronic stroke patients, which may reflect changes to early sensorimotor function. More research is required to investigate the long-term effects of chiropractic spinal manipulation, to better understand what impact it may have on the neurological function of stroke survivors.

Study protocol for a randomised double-blinded, sham-controlled, prospective, cross-over clinical trial of vagal neuromodulation for pain treatment in patients with chronic pancreatitis.

INTRODUCTION: The management of chronic pancreatitis (CP) is challenging and requires a personalised approach focused on the individual patient's main symptoms. Abdominal pain is the most prominent symptom in CP, where central pain mechanisms, including sensitisation and impaired pain modulation, often are involved. Recent clinical studies suggest that vagal nerve stimulation (VNS) induces analgesic effects through the modulation of central pain pathways. This study aims to investigate the effect of 2 weeks transcutaneous VNS (t-VNS) on clinical pain in patients with CP, in comparison to the effect of sham treatment. METHODS AND ANALYSIS: Twenty-one patients with CP will be enrolled in this randomised, double-blinded, single-centre, sham-controlled, cross-over study. The study has two treatment periods: A 2-week active t-VNS using GammaCore device and a 2-week treatment with a sham device. During both treatment periods, the patients are instructed to self-administer VNS bilaterally to the cervical vagal area, three times per day. Treatment periods will be separated by 2 weeks. During the study period, patients will record their daily pain experience in a diary (primary clinical endpoint). In addition, all subjects will undergo testing which will include MRI, quantitative sensory testing, cardiac vagal tone assessment and collecting blood samples, before and after the two treatments to investigate mechanisms underlying VNS effects. The data will be analysed using the principle of intention to treat. ETHICS AND DISSEMINATION: The regional ethics committee has approved the study: N-20170023. Results of the trial will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: The study is registered at www.clinicaltrials.gov: NCT03357029.

Cingulate glutamate levels associate with pain in chronic pancreatitis patients.

AIMS: Emerging evidence show that patients with chronic pancreatitis (CP) and abdominal pain have structural and functional alterations in the central nervous system. The aim was to investigate cerebral metabolic signatures in CP and the associations to various risk factors/clinical characteristics and patient outcomes. METHODS: Magnetic resonance spectroscopy was used to measure brain metabolites in the anterior cingulate cortex (ACC), insula, prefrontal cortex and the parietal region in patients with CP and healthy controls. Subgroup analyses based on disease characteristics (alcoholic etiology of CP, diabetes and opioid treatment) were performed. Finally, relations to abdominal pain symptoms and quality of life scores were explored. RESULTS: Thirty-one patients with CP (mean age 58.5 ±â€¯9.2 years) and 23 healthy controls (54.6 ±â€¯7.8 years) were included. Compared to healthy controls, patients had increased glutamate/creatine (glu/cre) levels in the ACC (1.24 ±â€¯0.17 vs. 1.13 ±â€¯0.21, p = .045) and reduced parietal N-acetylaspartate/creatine (NAA/cre) levels (1.44 ±â€¯0.18 vs. 1.54 ±â€¯0.12, p = .027). Patients with alcoholic etiology of CP had significant lower levels of parietal NAA/cre as compared to patients without alcoholic etiology and healthy controls (p < .006). Patients with a high level of ACC glu/cre reported more severe abdominal pain than their counterparts with a low level of ACC glu/cre (pain score 4.1 ±â€¯2.7 vs.1.9 ±â€¯2.3, p = .039). CONCLUSIONS: Cerebral spectroscopy revealed novel and complementary information on central pain mechanisms and alcohol mediated toxic effects in patients with CP. Our data suggest that cingulate glutamate levels associate with the patients clinical pain symptoms, while parietal NAA levels more likely associate with an alcoholic etiology of CP.

The effects of chiropractic spinal manipulation on central processing of tonic pain - a pilot study using standardized low-resolution brain electromagnetic tomography (sLORETA).

The objectives of the study were to investigate changes in pain perception and neural activity during tonic pain due to altered sensory input from the spine following chiropractic spinal adjustments. Fifteen participants with subclinical pain (recurrent spinal dysfunction such as mild pain, ache or stiffness but with no pain on the day of the experiment) participated in this randomized cross-over study involving a chiropractic spinal adjustment and a sham session, separated by 4.0 ± 4.2 days. Before and after each intervention, 61-channel electroencephalography (EEG) was recorded at rest and during 80 seconds of tonic pain evoked by the cold-pressor test (left hand immersed in 2 °C water). Participants rated the pain and unpleasantness to the cold-pressor test on two separate numerical rating scales. To study brain sources, sLORETA was performed on four EEG frequency bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz) and beta (12-32 Hz). The pain scores decreased by 9% after the sham intervention (p < 0.05), whereas the unpleasantness scores decreased by 7% after both interventions (p < 0.05). sLORETA showed decreased brain activity following tonic pain in all frequency bands after the sham intervention, whereas no change in activity was seen after the chiropractic spinal adjustment session. This study showed habituation to pain following the sham intervention, with no habituation occurring following the chiropractic intervention. This suggests that the chiropractic spinal adjustments may alter central processing of pain and unpleasantness.

Pregabalin reduces pain in patients with chronic pancreatitis in a randomized, controlled trial.

BACKGROUND & AIMS: Pain is a disabling symptom for patients with chronic pancreatitis (CP) and difficult to treat. Evidence from basic science and human studies indicates that pain processing by the central nervous system is abnormal and resembles that observed in patients with neuropathic pain disorders. We investigated whether agents used to treat patients with neuropathic pain are effective in CP. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate the effects of the gabapentoid pregabalin as an adjuvant analgesic. We measured pain relief, health status, quality of life, and tolerability in 64 patients with pain from CP; they were randomly assigned to groups given increasing doses of pregabalin or placebo (control) for 3 consecutive weeks. The primary end point was pain relief, based on a visual analogue scale documented by a pain diary. Secondary end points included Patients' Global Impression of Change (PGIC) score, changes in physical and functional scales, pain character, quality of life, and tolerability. RESULTS: Pregabalin, compared with placebo, caused more effective pain relief after 3 weeks of treatment (36% vs 24%; mean difference, 12%; 95% confidence interval, 22%-2%; P = .02). The percentage of patients with much or very much improved health status (PGIC score) at the end of the study was higher in the pregabalin than the control group (44% vs 21%; P = .048). Changes in physical and functional scales, pain character, quality of life, and number of serious adverse events were comparable between groups. CONCLUSIONS: In a placebo-controlled trial, pregabalin is an effective adjuvant therapy for pain in patients with CP.

Abnormal brain processing in hepatic encephalopathy: evidence of cerebral reorganization?

BACKGROUND AND AIM: Hepatic encephalopathy (HE) is a severe and frequent complication of liver cirrhosis characterized by abnormal cerebral function. Little is known about the underlying neural mechanisms in HE and human data are sparse. Electrophysiological methods such as evoked brain potentials after somatic stimuli can be combined with inverse modeling of the underlying brain activity. Thereby, information on neuronal dynamics and brain activity can be studied in vivo. The aim of this study was to investigate the sensory brain processing in patients with HE. PATIENTS AND METHODS: Twelve patients with minimal or overt HE and 26 healthy volunteers were included in the study. Cerebral sensory processing was investigated as (i) an auditory reaction time task; (ii) visual and somatosensory evoked brain potentials, and (iii) reconstruction of the underlying brain activity. RESULTS: Somatosensory evoked potentials were reproducible (all P>0.05), whereas flash evoked potentials were not reproducible (all P<0.05). Compared with healthy volunteers, the patient group had a prolonged reaction time index (P=0.03) along with increasing prolongation of latencies of median nerve evoked potentials (P<0.03). Reconstruction of the underlying brain sources showed a lateral shift in source localization of the P45 (P<0.001) and N60 components (P=0.02). A correlation between the psychometric hepatic encephalopathy score and the dipole shift corresponding to the N60 (P=0.003) component was seen. CONCLUSION: HE patients have evidence of prolonged intracerebral nerve conduction, along with lateralization of brain activity following median nerve stimulation. This possibly represents cortical reorganization and may be important in our understanding of this condition.

Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus.

Visceral afferents originating from different gut-segments converge at the spinal level. We hypothesized that chemically-induced hyperalgesia in the oesophagus could provoke widespread visceral hypersensitivity and also influence descending modulatory pain pathways. Fifteen healthy volunteers were studied at baseline, 30, 60 and 90 min after randomized perfusion of the distal oesophagus with either saline or 180 ml 0.1M HCl+2mg capsaicin. Electro-stimulation of the oesophagus, 8 cm proximal to the perfusion site, rectosigmoid electrical stimulation and rectal mechanical and heat stimulations were used. Evoked brain potentials were recorded after electrical stimulations before and after oesophageal perfusion. After the perfusion, rectal hyperalgesia to heat (P<0.01, 37%) and mechanical (P=0.01, 11%) stimulations were demonstrated. In contrast, hypoalgesia to electro-stimulation was observed in both the oesophagus (P<0.03, 23%) and the sigmoid colon (P<0.001, 18%). Referred pain areas to electro-stimulation in oesophagus were reduced by 13% after perfusion (P=0.01). Evoked brain potentials to rectosigmoid stimulations showed decreased latencies and amplitudes of P1, N1 and P2 (P<0.05), whereas oesophagus-evoked brain potentials were unaffected after perfusion. In conclusion, modality-specific hyperalgesia was demonstrated in the lower gut following chemical sensitization of the oesophagus, reflecting widespread central hyperexcitability. Conversely, hypoalgesia to electrical stimulation, decreases in referred pain and latencies of evoked brain potentials was seen. This outcome may reflect a counterbalancing activation of descending inhibitory pathways. As these findings are also seen in the clinical setting, the model may be usable for future basic and pharmacological studies.

Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin.

The present human study aimed at investigating the effect of subcutaneous administration of Botulinum toxin type A (BoNT/A) on capsaicin-induced trigeminal pain, neurogenic inflammation and experimentally induced cutaneous pain modalities. Fourteen healthy males (26.3+/-2.6 years) were included in this double-blind and placebo-controlled trial. The subjects received subcutaneous BoNT/A (22.5U) and isotonic saline in the mirror sides of their forehead. Pain and neurogenic inflammation was induced by four intradermal injections of capsaicin (100mug/muL) (before, and days 1, 3 and 7 after treatments). The capsaicin-induced pain intensity, pain area, the area of secondary hyperalgesia, the area of visible flare and vasomotor reactions were recorded together with cutaneous heat, electrical and pressure pain thresholds. BoNT/A reduced the capsaicin-induced trigeminal pain intensity compared to saline (F=37.9, P<0.001). The perceived pain area was smaller for the BoNT/A-treated side compared to saline (F=7.8, P<0.05). BoNT/A reduced the capsaicin-induced secondary hyperalgesia (F=5.3, P<0.05) and flare area (F=10.3, P<0.01) compared to saline. BoNT/A reduced blood flow (F(1,26)=109.5, P<0.001) and skin temperature (F(1,26)=63.1, P<0.001) at the capsaicin injection sites compared to saline and its suppressive effect was maximal at days 3 and 7 (P<0.05, post hoc test). BoNT/A elevated cutaneous heat pain thresholds (F=17.1, P<0.001) compared to saline; however, no alteration was recorded for electrical or pressure pain thresholds (P>0.05). Findings from the present study suggest that BoNT/A appears to preferentially target Cfibers and probably TRPV1-receptors, block neurotransmitter release and subsequently reduce pain, neurogenic inflammation and cutaneous heat pain threshold.