Jürg Schliessbach

The prevalence of widespread central hypersensitivity in chronic pain patients

Chronic pain is associated with generalized hypersensitivity and impaired endogenous pain modulation (conditioned pain modulation; CPM). Despite extensive research, their prevalence in chronic pain patients is unknown. This study investigated the prevalence and potential determinants of widespread central hypersensitivity and described the distribution of CPM in chronic pain patients.

Do central hypersensitivity and altered pain modulation predict the course of chronic low back and neck pain

Objectives:Widespread central hypersensitivity and altered conditioned pain modulation (CPM) have been documented in chronic pain conditions. Information on their prognostic values is limited. This study tested the hypothesis that widespread central hypersensitivity (WCH) and altered CPM, assessed during the chronic phase of low back and neck pain, predict poor outcome. Methods:A total of 169 consecutive patients with chronic low back or neck pain, referred to the pain clinic during 1 year, were analyzed. Pressure pain tolerance threshold at the second toe and tolerance time during cold pressor test at the hand assessed WCH. CPM was measured by the change in pressure pain tolerance threshold (test stimulus) after cold pressor test (conditioning stimulus). A structured telephone interview was performed 12 to 15 months after testing to record outcome parameters. Linear regression models were used, with average and maximum pain intensity of the last 24 hours at follow-up as endpoints. Multivariable analyses included sex, age, catastrophizing scale, Beck Depression Inventory, pain duration, intake of opioids, and type of pain syndrome. Results:Statistically significant reductions from baseline to follow-up were observed in pain intensity (P<0.001). No evidence for an association between the measures of WCH or CPM and intensity of chronic pain at follow-up was found. Discussion:A major predictive value of the measures that we used is unlikely. Future studies adopting other assessment modalities and possibly standardized treatments are needed to further elucidate the prognostic value of WCH and altered CPM in chronic pain.

Linking altered central pain processing and genetic polymorphism to drug efficacy in chronic low back pain.

BackgroundInability to predict the therapeutic effect of a drug in individual pain patients prolongs the process of drug and dose finding until satisfactory pharmacotherapy can be achieved. Many chronic pain conditions are associated with hypersensitivity of the nervous system or impaired endogenous pain modulation. Pharmacotherapy often aims at influencing these disturbed nociceptive processes. Its effect might therefore depend on the extent to which they are altered. Quantitative sensory testing (QST) can evaluate various aspects of pain processing and might therefore be able to predict the analgesic efficacy of a given drug. In the present study three drugs commonly used in the pharmacological management of chronic low back pain are investigated. The primary objective is to examine the ability of QST to predict pain reduction. As a secondary objective, the analgesic effects of these drugs and their effect on QST are evaluated.Methods/DesignIn this randomized, double blinded, placebo controlled cross-over study, patients with chronic low back pain are randomly assigned to imipramine, oxycodone or clobazam versus active placebo. QST is assessed at baseline, 1 and 2 h after drug administration. Pain intensity, side effects and patients’ global impression of change are assessed in intervals of 30 min up to two hours after drug intake. Baseline QST is used as explanatory variable to predict drug effect. The change in QST over time is analyzed to describe the pharmacodynamic effects of each drug on experimental pain modalities. Genetic polymorphisms are analyzed as co-variables.DiscussionPharmacotherapy is a mainstay in chronic pain treatment. Antidepressants, anticonvulsants and opioids are frequently prescribed in a “trial and error” fashion, without knowledge however, which drug suits best which patient. The present study addresses the important need to translate recent advances in pain research to clinical practice. Assessing the predictive value of central hypersensitivity and endogenous pain modulation could allow for the implementation of a mechanism-based treatment strategy in individual patients.Trial registrationClinicaltrials.gov, NCT01179828

Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity

See Dickenson (doi:10.1093/brain/awx334) for a scientific commentary on this article.Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans.

Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain

Abstract Introduction Quantitative sensory tests (QST) can be used for profiling anti-nociceptive effects of analgesics. However, anti-nociceptive effects detected by QST are not necessarily associated with analgesic effects in pain patients. As part of a large investigation on low back pain, this paper describes the immediate analgesic and anti-nociceptive effects of oxycodone in chronic low-back pain and ranks different QST according to their ability to reflect this effect. The results are expected to support the selection of QST for future studies on potential novel opioid agonists in human pain. Methods In this randomized, placebo-controlled and double-blinded cross-over study, 50 patients with chronic low-back pain received a single oral dose of oxycodone 15 mg or active placebo, and underwent multiple QST testing. The intensity of low-back pain was recorded during 2 h. The areas under the ROC curves and 95% confidence intervals were determined, whereby responder status (≤30% pain reduction) was set as reference variable and changes in QST from baseline were set as classifiers. Results Significant analgesic effect on low-back pain as well as anti-nociceptive effects for almost all QST parameters were observed. The QST with the highest area under the curve were heat pain detection threshold (0.65,95%-CI 0.46 to 0.83), single-stimulus electrical pain threshold (0.64,95%-CI 0.47 to 0.80) and pressure pain detection threshold (0.63,95%-CI 0.48 to 0.79). Conclusions The results suggest that anti-nociceptive effects assessed by QST fairly reflect clinical efficacy of oxycodone on low-back pain. Pressure pain detection threshold, heat pain detection threshold and single-stimulus electrical pain threshold may be more suitable to sort out potential non-responders rather than identifying potential responders to opioid medication. Future pre-clinical human research may consider these results when investigating the analgesic effect of opioid agonists by means of QST.

Analgesic effect of clobazam in chronic low-back pain but not in experimentally induced pain

Chronic pain is frequently associated with hypersensitivity of the nervous system, and drugs that increase central inhibition are therefore a potentially effective treatment. Benzodiazepines are potent modulators of GABAergic neurotransmission and are known to exert antihyperalgesic effects in rodents, but translation into patients are lacking. This study investigates the effect of the benzodiazepine clobazam in chronic low‐back pain in humans. The aim of this study is to explore the effect of GABA modulation on chronic low‐back pain and on quantitative sensory tests.

Effect of single-dose imipramine on chronic low-back and experimental pain: A randomized controlled trial

Antidepressants are frequently prescribed as co-analgesics in chronic pain. While their efficacy is well documented for neuropathic pain, the evidence is less clear in musculoskeletal pain conditions. The present study therefore evaluated the effect of the tricyclic antidepressant imipramine on chronic low-back pain in a randomized, double-blinded placebo-controlled design. To explore the mechanisms of action and the influence of drug metabolism, multimodal quantitative sensory tests (QST) and genotyping for cytochrome P450 2D6 (CYP2D6) were additionally performed. A single oral dose of imipramine 75 mg was compared to active placebo (tolterodine 1 mg) in 50 patients (32 females) with chronic non-specific low-back pain. Intensity of low-back pain was assessed on a 0–10 numeric rating scale at baseline and every 30 minutes after drug intake. Multimodal QST were performed at baseline and in hourly intervals for 2 hours. Pharmacogenetic influences of cytochrome P450 were addressed by CYP2D6 genotyping. No significant analgesic effect was detected neither on low-back pain nor on any of the sensory tests in the overall analyses. However, evidence for an interaction of the imipramine effect and CYP2D6 genotype was found for electrical and for pressure pain detection thresholds. Intermediate but not extensive metabolizers had a 1.20 times greater electrical pain threshold (95%-CI 1.10 to 1.31) and a 1.10 times greater pressure pain threshold (95%-CI 1.01 to 1.21) 60 minutes after imipramine than after placebo (p<0.001 and p = 0.034, respectively). The present study failed to demonstrate an immediate analgesic effect of imipramine on low-back pain. Anti-nociceptive effects as assessed by quantitative sensory tests may depend on CYP2D6 genotype, indicating that metabolizer status should be accounted for when future studies with tricyclic antidepressants are undertaken.

(415) Effect of the benzodiazepine clobazam in chronic low back pain and experimental pain modalities: a randomized placebo-controlled crossover study

GABAergic compounds enhance endogenous inhibitory control within the central nervous system and are therefore potentially useful in human pain conditions. Clobazam is an agonist at the benzodiazepine-binding site of GABA-A receptors. We investigated its effect on low back pain and experimental pain modalities in chronic low back pain. Forty-nine patients with chronic low back pain received a single oral dose of clobazam 20 mg and the active placebo tolterodine 1 mg in a double-blinded cross-over fashion. Pain intensity (0-10) (primary endpoint) was measured in the supine and sitting position. Nine experimental pain modalities of pressure, electrical and thermal pain, including conditioned pain modulation, were applied at body sites distant to the low back. All assessments were made during 2 hours after drug intake. Pain intensity in the supine position was significantly lower after clobazam compared to placebo (60 minutes: 2.9 vs. 3.5, p=0.008; 90 minutes: 2.7 vs. 3.3, p=0.024; 120 minutes: 2.4 vs. 3.1, p=0.005). Pain intensity in the sitting position was not significantly different between the groups. No effect on experimental pain tests was observed. The results are suggestive for an analgesic effect of clobazam in low back pain. The lack of effect in the sitting position suggests that GABAergic modulation may be less effective during mechanical strain of injured structures that may occur in the sitting position; the effect in the supine position suggests that GABAergic modulation is more effective at rest, when central sensitization processes may predominate over peripheral nociception. The lack of effect on experimental pain modalities suggests that GABAergic compounds may not be effective on non-sensitized neural pathways that are not functionally connected to the site of injury. The finding of the present study encourages pharmacologic research on GABAergic compounds that are devoid of tolerance and sedation. Funded by the Swiss National Science Foundation.

180 ANAESTHETIC BLOCK OF THE SINUVERTEBRAL NERVE: DIAGNOSTIC VALUE FOR DISCOGENIC PAIN AND MODULATION OF CENTRAL SENSITISATION

by a model of central sensitization (5 min/46oC). Heat pain (HP) was reported continuously on a 10 cm VAS. Area of secondary hyperalgesia (SHA) was assessed with a Von Frey filament. Results: Clinical NSP was significantly different between sessions: 1.9±1.4 cm on days with low NSP vs. 4.6±1.5 cm on days with high NSP (p < 0.001). SHA was not different between sessions: 52.1±13.5 cm vs. 52.2±14.3 cm (p =0.98). There was a significant correlation between perceived HP and development of SHA (p < 0.05). Conclusion: The difference in NSP indicate that we succeeded in recruiting subjects at different levels of clinical pain. However, the different levels of clinical pain did not predict development of cutaneous hyperalgesia. The results indicate that, with the present model, there is no increase in central sensibility during periods with high levels of deep-tissue pain.