Purpose Pain is a common symptom of acromegaly, impairing health-related quality of life (HR-QoL) significantly despite long-term disease remission. Neuropathic-like pain (NP-like) symptoms are... Show morePurpose Pain is a common symptom of acromegaly, impairing health-related quality of life (HR-QoL) significantly despite long-term disease remission. Neuropathic-like pain (NP-like) symptoms are invalidating, with great impact on HR-QoL. Studies characterizing or investigating the etiology of pain in acromegaly are scarce. Therefore, we aimed to assess NP-like symptoms in a cohort of controlled acromegaly patients. Methods Forty-four long-term controlled acromegaly patients (aged 62.6 +/- 12.6 years; 56.8% female) were included in this cross-sectional study. NP-like symptoms were assessed using the validated painDETECT questionnaire. Patients were divided in three probability-based NP-like symptoms categories based on the total score (range 0-35): unlikely (<= 12), indeterminate (13-18) and likely (>= 19). HR-QoL (physical component score (PCS), and mental component score (MCS)), and self-reported pain were assessed using Short Form-36 (SF-36). Potential risk factors were determined using linear regression analyses. Results Self-reported pain was reported by 35 patients (79.5%). Likely NP-like symptoms were present in 4/44 patients (9.1%), and indeterminate NP-like symptoms in 6/44 patients (13.6%). All patients with likely NP-like symptoms were female. Higher painDETECT scores were negatively associated with HR-QoL (PCS: r = - 0.46, P = 0.003; MCS: r = - 0.37, P = 0.018), and SF-36 pain scores (r = - 0.63, P < 0.0001). Female sex was a risk factor for NP-like symptoms. Conclusions Pain was prevalent in controlled acromegaly patients, whereas NP-like symptoms were relatively infrequent, and only observed in females. NP-like symptoms were associated with lower HR-QoL in acromegaly. Since specific analgesic therapy is available, awareness for characterization, increased understanding, and clinical trials regarding neuropathic pain identification and treatment in acromegaly patients are warranted. Show less
Velzen, M. van; Dahan, J.D.C.; Dorp, E.L.A. van; Mogil, J.S.; Hooijmans, C.R.; Dahan, A. 2021
In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed... Show moreIn humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous. Show less
Despite many advances in the last decades in understanding pain, the development of new analgesic compounds has not followed at the same pace. The development of more targeted analgesic compounds... Show moreDespite many advances in the last decades in understanding pain, the development of new analgesic compounds has not followed at the same pace. The development of more targeted analgesic compounds with fewer side effects is therefore essential. With an increased demand to demonstrate pharmacodynamic effects of new analgesic compounds, the importance of human evoked pain models is now higher than ever. Pharmacodynamic evaluation with human evoked pain models offers the possibility to determine the dose ranges at which new analgesics exert their pharmacological effect. Pain models may also aid in the choice of target population, determine which modality of pain a new drug is expected to be most suitable, help to differentiate between a central or more peripheral mode of action of new drugs, and help determine which other effects contribute to its mode of action e.g., sedation. Using pain models in healthy volunteers has important advantages over assessing the effects of new drugs in patients with pain; the pain elicited in human pain models is predictable in its intensity while clinical pain will naturally fluctuate. Analgesic properties can be investigated with pain models without the influence of accompanying symptoms that are often seen in patients with pain. Show less
Bechakra, M.; Nieuwenhoff, M.D.; Rosmalen, J. van; Groeneveld, G.J.; Huygen, F.J.P.M.; Zeeuw, C.I. de; ... ; Jongen, J.L.M. 2020
Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and... Show moreConsistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age -matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CLAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between LENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology. Show less
Neuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological... Show moreNeuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological treatment is often inadequate and coincides with intolerable side effects. The spared nerve injury animal model of neuropathic pain was employed as a method for evaluating the effect of the 11-amino acid tissue protective peptide ARA 290, and the NMDA receptor antagonist ketamine on behavioral and cellular responses after nerve injury and comparison of these two drugs. Clinically, pain is a subjective outcome that can be measured by numerical rating scales or questionnaires. Due to this subjectiveness it is not reliable for diagnosing small fiber neuropathy (SFN). Therefore, SFN is being diagnosed by invasive method of intra-epidermal nerve fiber density evaluated with microscopy. Alternatively, the cornea has a high density of small nerve fibers that can be evaluated by the non-invasive method of corneal confocal microscopy. Finally, the effect of ARA 290 on nerve fiber loss and corneal nerve fiber density in sarcoidosis patients in a double-blind-randomized clinical study was evaluated that showed that ARA 290 is a potential disease modifying agent for treatment of sarcoidosis-associated SNFLD. Show less
Chronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our... Show moreChronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our understanding of the mechanistic and molecular basis of pain, chronic pain remains a significant clinical problem that has few effective therapies Throughout the various chapters we have highlighted some important conceptual and experimental flaws in the way that pain signalling and pharmacological activity are characterised and translated across species and disease conditions. The common denominator of the work presented here is the requirement for accurate characterisation of exposure-response relationships, without which the dose rationale for the progression of a molecule cannot justified, whether drugs are aimed at symptomatic relief, disease modification or prophylaxis. In addition to a comprehensive review of the mechanisms underlying pain signalling and symptoms, the work developed here focuses on three different aspects of research underpinning the use of pharmacokinetic-pharmacodynamic relationships. First, we have explored the requirements for the characterisation of behavioural measures of pain during the early screening of candidate molecules, shedding light onto the shortcomings of experimental protocols commonly used in preclinical research. Then we introduced the prerequisites for the parameterisation of pain behaviour to ensure accurate translation of the pharmacological properties across species as well as for bridging across different phases of development. Lastly, an attempt was made to model clinical response in chronic inflammatory pain and to establish correlations between symptom improvement and the underlying pharmacological effects using biomarkers. In addition our work showed how clinical trial simulations can be used as a design tool, enabling the evaluation of a variety of scenarios that disentangle the contribution of pharmacology from the confounding effects of placebo and disease dynamics. Show less
Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterised by pain and disturbed blood flow, temperature regulation and motor control. Knowledge on CRPS... Show moreComplex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterised by pain and disturbed blood flow, temperature regulation and motor control. Knowledge on CRPS and its movement disorders is scarce. Dysfunction in small nerve fiber processing was found in CRPS patients with dystonia. Furthermore, a dominant pattern of fixed dystonia was observed in two thirds of arms and legs: finger flexion, wrist flexion, elbow flexion and/or shoulder adduction; and ankle plantar flexion/inversion, toe flexion, knee flexion and/or hip internal rotation. A modelling study demonstrated that aberrant force feedback from Golgi tendon organs may be a factor. Cerebrospinal fluid findings did not support a role of inflammatory mediators in chronic CRPS-related dystonia. Characteristics of CRPS-related myoclonus were diverse. One intrathecal administration of methylprednisolone was not efficacious in chronic CRPS. Also, continuous intrathecal glycine showed no efficacy in CRPS-related dystonia. However, intrathecal baclofen reduced severity of CRPS-related dystonia, improved quality of life and remained efficacious over a period of one year. The findings lend support to the role of GABA (gamma aminobutyric acid)-ergic mechanisms in this cause of dystonia. The findings stimulate new directions of research on this topic. Show less
