Volume 4, Issue 3

Background Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel permeable to calcium that is expressed on pain-mediating primary afferent nerve fibers. Here we review recent experimental evidence supporting the hypothesis that activation of the TRPA1 channel by reactive compounds generated in diabetes mellitus, such as 4-hydroxynonenal and methylglyoxal, exerts an important role in the pathophysiology of peripheral diabetic neuropathy (PDN). The hypothesis includes development of the early diabetic pain hypersensitivity and the later loss of cutaneous nerve endings of pain fibers and their dysfunction, which are hallmarks of peripheral diabetic neuropathy (PDN). Methods The evidence for a role of the TRPA1 channel in PDN consists of in vitro patch clamp and calcium imaging data and assessments of pain behavior, axon reflex measurements, and immunohistochemical analyses of cutaneous innervation in an experimental animal model of diabetes. The experiments were combined with blocking the TRPA1 channel with selective antagonists Chembridge-5861528 or A-967079. Results In vitro studies indicate that under physiological concentration of Ca 2+ , methylglyoxal and 4-hydroxynonenal produce sustained activation of the TRPA1 channel and sustained inflow of calcium. In vivo studies indicate that diabetic pain hypersensitivity is maintained by the TRPA1 channel as indicated by the antihypersensitivity effect induced by acute blocking of the TRPA1 channel. Moreover, TRPA1 channel is involved in the development of diabetic hypersensitivity as indicated by prevention of the development of pain hypersensitivity in diabetic animals treated daily with Chembridge-5861528. The diabetes-induced loss of substance P-like cutaneous innervation and that of the TRPA1 channel-mediated cutaneous axon reflex function during the later phase of diabetes were also prevented or delayed by prolonged blocking of the TRPA1 channel. No motor impairment or other obvious side-effects were observed following block of the TRPA1 channel. Conclusions Together the in vitro and in vivo results indicate that reactive compounds generated in diabetes exert, through action on the TRPA1 channel, an important role in the pathophysiology of PDN. Sustained activation of the TRPA1 channel is a plausible mechanism that contributes to the early diabetic pain hypersensitivity and the later loss of cutaneous pain fiber endings and their dysfunction with prolonged diabetes. Implications Blocking the TRPA1 channel with a selective antagonist provides a promising disease-modifying treatment for PDN, with only minor, if any, side-effects.

Background and aims Peripheral neuropathic pain (PNeP) is a chronic and disabling condition for which no predictors of response to treatment have yet been identified. Clinical studies show that while many patients with PNeP respond positively to treatment with the capsaicin 8% patch, others do not. This study used quantitative sensory testing (QST) to determine whether any patient characteristics can predict response to treatment with the capsaicin 8% patch. Methods This was a prospective, non-placebo-controlled, observational study. Patients used the Visual Analogue Scale (VAS) to assess their pain at baseline and then on Days 1, 7–10 (from here referred to as Day 7/10), 28 and 84 following treatment with the capsaicin 8% patch. QST was undertaken at the same timepoints on the painful area at the region of maximum PNeP and on a contralateral, control area. In addition, the size of the painful area was assessed at baseline and Days 7/10, 28 and 84. Results A total of 57 patients were treated. Among 54 evaluable patients, 19 (35.2%) achieved a ≥30% reduction in VAS pain score at Day 7/10 post-treatment compared with baseline — these were defined as ‘responders’. Analysis of the QST data showed that the PNeP area in responders, but not in non-responders, had a significantly lower pressure pain threshold compared with the control area at baseline (median 320 kPa vs. 480 kPa, respectively; p = .004). Furthermore, non-responders had approximately three times greater degree of allodynia at baseline compared with responders across tests using brush, cotton wool and Q-tip. These differences were significant for tests using brush and cotton wool ( p = .024 and p = .046, respectively) and approached significance in the test using Q-tip ( p = .066). Following treatment with the capsaicin 8% patch, responders showed a trend towards a reduction in warm perception and also appeared to show normalization of the pinprick hyperalgesia at some stimulus levels. Responders to therapy had significantly greater reductions than non-responders in the size of the painful area at Day 28 ( p = .011) and Day 84 ( p = .005) following treatment. However, both responders and non-responders had meaningful reductions in the size of the painful area compared with baseline values. Conclusions This study suggests that differences can be identified in the sensory profiles of patients with PNeP who respond to the capsaicin 8% patch and those who do not, specifically pressure pain threshold and degree of allodynia. Notably, both responders and non-responders experienced meaningful reductions in the size of the painful area following treatment. Implications The findings warrant further investigation in a larger number of patients and in prospective trials.

Background There are a number of false myths about buprenorphine based on unconfirmed animal data, even from isolated animal organs, and early clinical research. These myths came into textbooks on pharmacology and pain about 30 years ago and have been difficult to eradicate. Animal models of pain and pain relief are notoriously unreliable as predictors of human clinical effects. The fact is that in clinical practice there is NO bell-shaped dose-response curve, there is NO plateau on the dose-response curve, and there is NO antagonist effect from buprenorphine on other mu -opioid agonists. Methods This narrative, topical review of relevant research publications evaluates new knowledge on the pharmacodynamics and pharmacokinetics of buprenorphine of importance in clinical practice. Results Buprenorphine is a potent opioid analgesic acting on all four opioid receptors: it is an agonist on the mu -, the delta , and the ORL-1 receptors. It is an antagonist at the kappa -receptor. Buprenorphine has a number of active metabolites with different effects on the four opioid receptors; all except the norbup-3-glu are analgesic. Buprenorphine itself is not a respiratory depressant or sedative, but some of its active metabolites are. Buprenorphine and its active metabolites are not excreted by the kidney. Therefore buprenorphine may be used in patients with advanced renal failure. Buprenorphine has a slow onset and a long offset. These properties are advantageous, except sometimes when treating severe acute pain. Its agonist effect on the ORL-1 receptor reduces reward-effects and slows the development of tolerance to the analgesic effects. Buprenorphine inhibits voltage-gated sodium-channels and enhances and prolongs peripheral nerve blocks. Its ORL-1 -effect at the spinal cord may do the same. Buprenorphine is well suited for treatment of chronic pain, especially chronic neuropathic pain and cancer pain. The beneficial effects as a co-medication during treatment of the opioid-abuse disease are due to its slow onset (less “kick-effect”). Its prolonged offset-time reduces the likelihood of acute withdrawal problems and reduces the “craving” of opioids. Adverse effects Buprenorphine, being a mu -agonist, may induce or maintain opioid addiction. Illegally obtained high-dose transmucosal buprenorphine, intended for treatment of addiction, is dissolved and injected by opioid abusers. This is an increasing problem in some countries. Conclusions Buprenorphine’s unusual pharmacodynamics and pharmacokinetics make it an ideal opioid for treatment of most chronic pain conditions where opioid therapy is indicated. Implications Buprenorphine is a well studied and often misunderstood analgesic opioid drug. The evidence base predicts that it will be an increasingly important alternative for treatment of chronic pain conditions caused by cancer and non-cancer diseases. It will continue to be an attractive alternative to methadone for opioid abuse rehabilitation.

Graphical abstract Isometric low load pain tolerance test position. Abstract Background and purpose Nirschl’s lateral epicondylalgia (LE) classification appears prognostic but is based upon an outdated model of tendinopathy. Psychosocial factors which may negatively influence treatment outcomes, central nervous system mediated hypersensitivity and motor impairment all occur in epicondylalgia. This study examines psychosocial/personality factors and physical measures in LE correlating them with Nirschl’s sub-groups. Methods Fifty-four subjects with LE and 43 healthy controls, recruited from primary care in Norway were assessed. Measures included: pressure pain threshold (PPT), isometric maximal load pain tolerance (MLT) and isometric low load (sustained hold of 0.5 kg weight) pain tolerance (LLT) of the wrist extensors, all of which were undertaken bilaterally; the Örebro Musculoskeletal Pain Questionnaire (ÖMPSQ), and the Swedish Scales of Personality. Results Patients had significantly lower pain thresholds than controls especially at the common extensor origin, but thresholds did not differentiate Nirschl’s groups. MLT did not differentiate between controls and patients or between pain groups. LLT differentiated pain patients from controls but not between different pain groups. The ÖMPSQ score was significantly different between three out of four of Nirschl’s pain groups and both pain thresholds and MLT in both the painful and non-/less painful arms were significantly but negatively correlated with the ÖMPSQ score. Somatic anxiety was significantly different between healthy controls and Nirschl’s most symptomatic pain group; and also correlated with the OMPSQ score. Conclusions The ÖMPSQ differentiated Nirschl’s sub-groups more effectively than the PPT, MLT or LLT, but the control group did not complete the ÖMPSQ, so a comparison of the subjects with LE to symptom-free subjects was not possible. Elevated somatic anxiety in the most symptomatic patients may indicate possible alexithymia or an inability to understand or cope with somatic symptoms of distress. The subjects in this study with epicondylalgia exhibited widespread, likely central nervous system mediated hypersensitivity, motor impairment and psychosocial factors in keeping with a modern model of LE. This hypersensitivity suggests epicondylalgia should not be considered a localised pathology and management should be tailored towards underlying multidimensional biopsychosocial pain mechanisms. Possible pain mechanisms driving this hypersensitivity are postulated. LLT, a novel impairment test, is significantly reduced in LE and should be examined in this patient group, and possibly rehabilitated specifically. Based upon physical and psychological data from this study, Nirschl’s sub-grouping seems too detailed and our results suggest that the four groups should be reduced to two. Thus, for diagnostic purposes the Nirschl’s groups I and II could be collapsed to one group, and groups III and IV to a second group. Implications Psychosocial and personality factors should be measured in subjects with epicondylalgia as they correlate with physical signs. Management should therefore be tailored to patient presentations, particularly where significant psychosocial factors or specific motor impairments exist.

Background and purpose Visceral and somatic afferents activate the same neuronal structures in the central nervous system. Assessing somatosensory function and trophic changes in the referred pain area may therefore indirectly increase information on mechanisms involved in painful visceral diseases. The aim of this study was to evaluate the sensory and trophic changes in the flank corresponding to the referred pain area in patients with kidney stone disease. Methods A total of 24 patients with unilateral pain-causing kidney stone disease were studied before and after endoscopic percutaneous kidney stone surgery. Trophic changes and sensitivity on the affected and on the contra-lateral side in the pain free period were investigated. For this purpose we used standardized experimental sensory testing including pressure stimulation and electrical (single and repeated) skin stimulation. Five repeated stimuli were used to investigate temporal summation (increased responses to repeated stimuli). To investigate trophic changes ultrasound as well as CT-scan was used, since the latter is considered more precise for exact tissue layer measurements. Results The pain tolerance thresholds to pressure and pain thresholds to electrical stimulation were not significantly different on the two sides (all P >0.1). After surgery no significant alterations in sensitivity were detected, but there was a tendency to higher pain thresholds to electrical stimuli on the affected side (single stimuli P =0.06; repeated stimuli P =0.09). No trophic changes were observed (all P >0.3), and there were no relations between the pain thresholds or trophic findings and the number of colics (all P >0.08). Conclusion In patients with unilateral pain-causing kidney stone disease the pain to experimental pressure and electrical stimuli were comparable on the affected and contra-lateral side. For the first time a CT-scan was used to evaluate tissue thickness in the referred pain area. No trophic changes were seen in the muscle or subcutaneous tissue at the affected side, and there were no correlations between the pain thresholds or trophic findings and the patients history of number of colics. After the operation no significant alterations in sensitivity were detected. Implications This study could not confirm previous studies showing referred hyperalgesia in the skin and trophic changes in the referred pain area to painful visceral disease. Differences in the pain intensity/duration between different diseases and hence the corresponding central neuronal changes may explain the negative findings in the present study.