GABAergic modulation in central sensitization in humans: a randomized placebo-controlled pharmacokinetic-pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers

Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.

Reference values of mechanical and thermal pain tests in a pain-free population

Quantitative sensory tests are widely used in human research to evaluate the effect of analgesics and explore altered pain mechanisms, such as central sensitization. In order to apply these tests in clinical practice, knowledge of reference values is essential. The aim of this study was to determine the reference values of pain thresholds for mechanical and thermal stimuli, as well as withdrawal time for the cold pressor test in 300 pain-free subjects. Pain detection and pain tolerance thresholds to pressure, heat and cold were determined at three body sites: (1) lower back, (2) suprascapular region and (3) second toe (for pressure) or the lateral aspect of the leg (for heat and cold). The influences of gender, age, height, weight, body-mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short-Form 36 (SF-36) were analyzed by multiple regressions. Quantile regressions were performed to define the 5th, 10th and 25th percentiles as reference values for pain hypersensitivity and the 75th, 90th and 95th percentiles as reference values for pain hyposensitivity. Gender, age and/or the interaction of age with gender were the only variables that consistently affected the pain measures. Women were more pain sensitive than men. However, the influence of gender decreased with increasing age. In conclusion, normative values of parameters related to pressure, heat and cold pain stimuli were determined. Reference values have to be stratified by body region, gender and age. The determination of these reference values will now allow the clinical application of the tests for detecting abnormal pain reactions in individual patients.

[Pathophysiology of abdominal pain]

Abdominal pain can be induced by stimulation of visceral nociceptors. Activation of nociceptors usually requires previous sensitization by pathological events, such as inflammation, ischemia or acidosis. Although abdominal pain can obviously be caused by pathology of a visceral structure, clinicians frequently observe that such a pathology explains only part of the pain complaints. Occasionally, there is lack of objective signs of visceral lesions. There is clear evidence that pain states are associated with profound changes of the central processing of the sensory input. The main consequences of such alterations for patients are twofold: 1) a central sensitization, i.e. an increased excitability of the central nervous system; 2) an alteration of the endogenous pain modulation, which under normal conditions inhibits the processing of nociceptive signals in the central nervous system. Both phenomena lead to a spread of pain to other body regions and an amplification of the pain perception. The interactions between visceral pathology and alterations of the central pain processes represent an at least partial explanation for the discrepancy between objective signs of peripheral lesions and severity of the symptoms. Today, both central hypersensitivity and alteration in endogenous pain modulation can be measured in clinical practice. This information can be used to provide the patients with an explanatory model for their pain. Furthermore, first data suggest that alterations in central pain processing may represent negative prognostic factors. A better understanding of the individual pathophysiology may allow in the future the development of individual therapeutic strategies.

[Drug therapy of acute and chronic abdominal pain]

For drug therapy a differentiation of acute and chronic pain is essential. In emergency situations of acute abdominal pain a fast diagnosis is mandatory. Analgesia should be provided as soon as possible. The different groups of analgesics should be used according to their known effects, side effects and contraindications. Postoperative pain after abdominal surgery has to be considered as a special condition of acute abdominal pain. Main treatment options are non opioid analgesics and opioids. Opioids can be administered intravenously via patient controlled analgesia (PCA) devices. In major abdominal surgery neuroaxial analgesia, preferentially administered via an epidural catheter provides excellent pain relief with positive impact on gastrointestinal motility and patients' recovery. Because of difficulties to allocate chronic abdominal pain to a specific organ, causal treatment often turns out to be difficult. Peripheral and central sensitization, as well as an alteration of the endogenous pain modulation comes to the fore in these chronic pain conditions. Co-analgesics like anticonvulsants and antidepressants are utilized to reduce sensitization and improve the endogenous pain modulating system. Non drug approaches and alternative treatment options might be useful. In contrast, orally or transcutaneously administered opioids are the principal corner stone for the treatment of cancer pain.

Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds

BACKGROUND: Calcitonin was effective in a study of acute phantom limb pain, but it was not studied in the chronic phase. The overall literature on N-methyl-D-aspartate antagonists is equivocal. We tested the hypothesis that calcitonin, ketamine, and their combination are effective in treating chronic phantom limb pain. Our secondary aim was to improve our understanding of the mechanisms of action of the investigated drugs using quantitative sensory testing. METHODS: Twenty patients received, in a randomized, double-blind, crossover manner, 4 i.v. infusions of: 200 IE calcitonin; ketamine 0.4 mg/kg (only 10 patients); 200 IE of calcitonin combined with ketamine 0.4 mg/kg; placebo, 0.9% saline. Intensity of phantom pain (visual analog scale) was recorded before, during, at the end, and the 48 h after each infusion. Pain thresholds after electrical, thermal, and pressure stimulation were recorded before and during each infusion. RESULTS: Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. There was no difference in basal pain thresholds between the amputated and contralateral side except for pressure pain. Pain thresholds were unaffected by calcitonin. The analgesic effect of the combination of calcitonin and ketamine was associated with a significant increase in electrical thresholds, but with no change in pressure and heat thresholds. CONCLUSIONS: Our results question the usefulness of calcitonin in chronic phantom limb pain and stress the potential interest of N-methyl-D-aspartate antagonists. Sensory assessments indicated that peripheral mechanisms are unlikely important determinants of phantom limb pain. Ketamine, but not calcitonin, affects central sensitization processes that are probably involved in the pathophysiology of phantom limb pain.

Ranking of tests for pain hypersensitivity according to their discriminative ability in chronic neck pain

BACKGROUND AND OBJECTIVES Quantitative sensory testing (QST) is widely used to investigate peripheral and central sensitization. However, the comparative performance of different QST for diagnostic or prognostic purposes is unclear. We explored the discriminative ability of different quantitative sensory tests in distinguishing between patients with chronic neck pain and pain-free control subjects and ranked these tests according to the extent of their association with pain hypersensitivity. METHODS We performed a case-control study in 40 patients and 300 control subjects. Twenty-six tests, including different modalities of pressure, heat, cold, and electrical stimulation, were used. As measures of discrimination, we estimated receiver operating characteristic curves and likelihood ratios. RESULTS The following quantitative sensory tests displayed the best discriminative value: (1) pressure pain threshold at the site of the most severe neck pain (fitted area under the receiver operating characteristic curve, 0.92), (2) reflex threshold to single electrical stimulation (0.90), (3) pain threshold to single electrical stimulation (0.89), (4) pain threshold to repeated electrical stimulation (0.87), and (5) pressure pain tolerance threshold at the site of the most severe neck pain (0.86). Only the first 3 could be used for both ruling in and out pain hypersensitivity. CONCLUSIONS Pressure stimulation at the site of the most severe pain and parameters of electrical stimulation were the most appropriate QST to distinguish between patients with chronic neck pain and asymptomatic control subjects. These findings may be used to select the tests in future diagnostic and longitudinal prognostic studies on patients with neck pain and to optimize the assessment of localized and spreading sensitization in chronic pain patients.

Inflammation and nerve fiber interaction in endometriotic pain.

Endometriosis is an extremely prevalent estrogen-dependent condition characterized by the growth of ectopic endometrial tissue outside the uterine cavity, and is often presented with severe pain. Although the relationship between lesion and pain remains unclear, nerve fibers found in close proximity to endometriotic lesions may be related to pain. Also, women with endometriosis pain develop central sensitization. Endometriosis creates an inflammatory environment and recent research is beginning to elucidate the role of inflammation in stimulating peripheral nerve sensitization. In this review, we discuss endometriosis-associated inflammation, peripheral nerve fibers, and assess their potential mechanism of interaction. We propose that an interaction between lesions and nerve fibers, mediated by inflammation, may be important in endometriosis-associated pain.

[Therapy of disorders with central pain sensitization.]

Previous somatic pain experience (priming), psychobiographic imprinting (pain proneness), and stress (action proneness) are key to an enhanced centralised pain response. This centralised pain response clinically manifests itself in pain sensitization and chronification. The therapeutic approach to chronic centralised pain disorders is multimodal. The overarching aim of the various interventions of a multimodal treatment program is to activate anti-nociceptive areas of the cerebral matrix involved in pain processing. The lists of medications targeting neuropathic and somatoform pain disorder show considerable overlap. Psychotherapy helps patients with central pain sensitization to improve pain control, emotional regulation and pain behaviour.