Anne Estrup Olesen

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain

A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes.

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials.

Opioid-induced Bowel Dysfunction: Pathophysiology and Management

Opioids are the most commonly prescribed medications to treat severe pain in the Western world. It has been estimated that up to 90% of American patients presenting to specialized pain centres are treated with opioids. Along with their analgesic properties, opioids have the potential to produce substantial side effects, such as nausea, cognitive impairment, addiction and urinary retention. In the gut, opioids exert their action on the enteric nervous system, where they bind to the myenteric and submucosal plexuses, causing dysmotility, decreased fluid secretion and sphincter dysfunction, which all leads to opioid-induced bowel dysfunction (OIBD). In the clinic, this is reported as nausea, vomiting, gastro-oesophageal reflux-related symptoms, constipation, etc.One of the most severe symptoms is constipation, which can be assessed using different scales for subjective assessment. Objective methods such as radiography and colonic transit time can also be used, together with manometry and evaluation of anorectal function to explore the pathophysiology.Dose-limiting adverse symptoms of OIBD can lead to insufficient pain treatment. Even though several treatment strategies are available, the side effects are still a major challenge. Traditional laxatives are normally prescribed but they are often insufficient to alleviate symptoms, especially those from the upper gastrointestinal tract. Newer prokinetics, such as prucalopride and lubiprostone, may be more effective in alleviating OIBD. Another treatment approach is co-administration of opioid antagonists, which either cannot cross the blood-brain barrier or selectively target opioid receptors in the gastrointestinal tract. However, although these new agents have proved to be more efficacious than placebo, clinical trials still need to prove their superiority to standard co-prescribed laxative regimes.

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

AIM Experimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed. METHOD A literature search was completed for randomized controlled studies which included human experimental pain models, healthy volunteers and opioids. RESULTS Opioids with a strong affinity for the micro-opioid receptor decreased the sensation in a variety of experimental pain modalities, but strong tonic pain was attenuated more than short lasting pain and non-painful sensations. The effects of opioids with weaker affinity for the micro-opioid receptor were detected by a more narrow range of pain models, and the assessment methods needed to be more sensitive. CONCLUSION The way the pain is induced, assessed and summarized is very important for the sensitivity of the pain models. This review gives an overview of how different opioids perform in experimental pain models. Generally experimental pain models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. This knowledge can aid the decisions needed to be taken when designing experimental pain studies for compounds entering phase 1 clinical trials.

Analgesic Efficacy of Peripheral κ-Opioid Receptor Agonist CR665 Compared to Oxycodone in a Multi-modal, Multi-tissue Experimental Human Pain Model: Selective Effect on Visceral Pain

Background:Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide &kgr;-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid). Methods:The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing. Results:Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007). Conclusion:CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review

AIM Experimental pain models may help to evaluate the mechanisms of analgesics and target the clinical indications for their use. This review, the second in a series of two, addresses how the efficacy of non-opioid analgesics have been assessed in human volunteers using experimental pain models. METHODS A literature search was completed for randomized controlled studies that included human experimental pain models, healthy volunteers and non-opioid analgesics. RESULTS Nonsteroidal anti-inflammatory drugs worked against various types of acute pain as well as in hyperalgesia. Analgesia from paracetamol was difficult to detect in experimental pain and the pain needed to be assessed with very sensitive methods like evoked brain potentials. The N-methyl-D-aspartate antagonists exemplified by ketamine generally needed strong, long-lasting or repeated pain in the skin for detectable analgesia, whereas pain in muscle and viscera generally was more easily attenuated. Gabapentin worked well in several models, particularly those inducing hyperalgesia, whereas lamotrigine was weak in modulation of experimental pain. Imipramine attenuated pain in most experimental models, whereas amitriptyline had weaker effects. Delta-9-tetrahydrocannabinol attenuated pain in only a few models. CONCLUSIONS Pain induction and assessment are very important for the sensitivity of the pain models. Generally, experimental pain models need to be designed with careful consideration of the pharmacological mechanisms and pharmacokinetics of analgesics. The drawback with the different study designs is also discussed. This knowledge can aid the decisions that need to be taken when designing experimental pain studies for compounds entering Phase I and II trials.

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.

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 0.1 M HCl + 2 mg 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.

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

Can quantitative sensory testing predict responses to analgesic treatment

The role of quantitative sensory testing (QST) in prediction of analgesic effect in humans is scarcely investigated. This updated review assesses the effectiveness in predicting analgesic effects in healthy volunteers, surgical patients and patients with chronic pain. A systematic review of English written, peer‐reviewed articles was conducted using PubMed and Embase (1980–2013). Additional studies were identified by chain searching. Search terms included ‘quantitative sensory testing’, ‘sensory testing’ and ‘analgesics’. Studies on the relationship between QST and response to analgesic treatment in human adults were included. Appraisal of the methodological quality of the included studies was based on evaluative criteria for prognostic studies. Fourteen studies (including 720 individuals) met the inclusion criteria. Significant correlations were observed between responses to analgesics and several QST parameters including (1) heat pain threshold in experimental human pain, (2) electrical and heat pain thresholds, pressure pain tolerance and suprathreshold heat pain in surgical patients, and (3) electrical and heat pain threshold and conditioned pain modulation in patients with chronic pain. Heterogeneity among studies was observed especially with regard to application of QST and type and use of analgesics. Although promising, the current evidence is not sufficiently robust to recommend the use of any specific QST parameter in predicting analgesic response. Future studies should focus on a range of different experimental pain modalities rather than a single static pain stimulation paradigm.