James L Henry

Forced mobilization accelerates pathogenesis: characterization of a preclinical surgical model of osteoarthritis

Preclinical osteoarthritis (OA) models are often employed in studies investigating disease-modifying OA drugs (DMOADs). In this study we present a comprehensive, longitudinal evaluation of OA pathogenesis in a rat model of OA, including histologic and biochemical analyses of articular cartilage degradation and assessment of subchondral bone sclerosis. Male Sprague-Dawley rats underwent joint destabilization surgery by anterior cruciate ligament transection and partial medial meniscectomy. The contralateral joint was evaluated as a secondary treatment, and sham surgery was performed in a separate group of animals (controls). Furthermore, the effects of walking on a rotating cylinder (to force mobilization of the joint) on OA pathogenesis were assessed. Destabilization-induced OA was investigated at several time points up to 20 weeks after surgery using Osteoarthritis Research Society International histopathology scores, in vivo micro-computed tomography (CT) volumetric bone mineral density analysis, and biochemical analysis of type II collagen breakdown using the CTX II biomarker. Expression of hypertrophic chondrocyte markers was also assessed in articular cartilage. Cartilage degradation, subchondral changes, and subchondral bone loss were observed as early as 2 weeks after surgery, with considerable correlation to that seen in human OA. We found excellent correlation between histologic changes and micro-CT analysis of underlying bone, which reflected properties of human OA, and identified additional molecular changes that enhance our understanding of OA pathogenesis. Interestingly, forced mobilization exercise accelerated OA progression. Minor OA activity was also observed in the contralateral joint, including proteoglycan loss. Finally, we observed increased chondrocyte hypertrophy during pathogenesis. We conclude that forced mobilization accelerates OA damage in the destabilized joint. This surgical model of OA with forced mobilization is suitable for longitudinal preclinical studies, and it is well adapted for investigation of both early and late stages of OA. The time course of OA progression can be modulated through the use of forced mobilization.

The Need for Knowledge Translation in Chronic Pain

One in five Canadians suffers from some form of persistent or chronic pain. The impact on individual lives, families and friends, the health services sector and the economy is huge. Reliable evidence is available that the burden of persistent pain can be markedly reduced when available knowledge is applied. Bridging the quality chasm between chronic pain and the care process will require a unique confluence of opinion from all stakeholders committed within a focused community of practice to address the impact of pain. Various levels of success in this regard have been demonstrated when there is exchange, synthesis and ethically sound application of research findings within a complex set of interactions among researchers and knowledge users. It is now critical to accelerate the capture of the benefits of research for Canadians through improved health, more effective and responsive services and products, and a strengthened health care system to bring about health reform and health care reform across Canada as it pertains to the one in five Canadians living with chronic, disabling pain. The overarching outcome of such an initiative needs to be promoted to sustain a balanced portfolio of curiosity- and needs-based research, which along with existing knowledge, can be mobilized and applied for the benefit of Canadians, the health care system and the economy.

Central Poststroke Pain: An Abstruse Outcome

Central poststroke pain (CPSP), formerly known as thalamic pain syndrome of Déjerine and Roussy, is a central neuropathic pain occurring in patients affected by stroke. It is one manifestation of central pain, which is broadly defined as central neuropathic pain caused by lesions or dysfunction in the central nervous system. Thalamic pain was first described 100 years ago by Déjerine and Roussy and has been described as among the most spectacular, distressing, and intractable of pain syndromes. CPSP is characterized by constant or intermittent pain and is associated with sensory abnormalities, particularly of thermal sensation. While the pain is frequently described as burning, scalding, or burning and freezing, other symptoms are usually vague and hard to characterize, making an early diagnosis particularly difficult. In fact, those who develop CPSP may no longer be under the care of health care professionals when their symptoms begin to manifest, resulting in misdiagnosis or a significant delay before treatment begins. Diagnosis is further complicated by cognitive and speech limitations that may occur following stroke, as well as by depression, anxiety and sleep disturbances. Patients may also exhibit spontaneous dysesthesia and the stimulus-evoked sensory disturbances of dysesthesia, allodynia and hyperalgesia. The present study offers a historical reference point for future clinical and basic research into this elusive type of debilitating pain.

iCanCope with Pain™: User-Centred Design of a Web- and Mobile-Based Self-Management Program for Youth with Chronic Pain Based on Identified Health Care Needs

Chronic pain self-management involves providing patients with knowledge, coping strategies and social support that help them to manage their pain. This type of intervention has been shown to be useful in treating chronic pain; however, many eligible chronic pain patients never receive such treatment due to limited accessibility and high cost. The use of Internet-based cognitive behavioural therapy has the potential to change this. In this study, the authors report their progress in the development of an Internet- and smartphone-based application for chronic pain self-management.

Molecular and Histological Analysis of a New Rat Model of Experimental Knee Osteoarthritis

Abstract:u2002 Articular cartilage degeneration is the most consistently observed feature of osteoarthritis (OA). Animal and human studies have shown that various forms of exercise influence the course of the disease in different ways. In addition, early changes in articular cartilage that influence the progression of OA, such as the expression of cytokines, require further investigation. We have used a surgically induced experimental model of knee OA to address these questions. Here, we discuss our recent studies investigating the effects of an exercise paradigm in surgically induced OA, which determined that the destabilized knee joint is susceptible to enhanced degeneration when subjected to low‐intensity, low‐impact exercise. Further, we investigated early global changes in gene expression in articular chondrocytes from degenerating cartilage. Identified candidate genes including genes involved in chemokine, endothelin, and transforming growth factor‐α signaling are discussed in the context of articular cartilage degeneration in early OA.

Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy

BackgroundCauses of neuropathic pain following nerve injury remain unclear, limiting the development of mechanism-based therapeutic approaches. Animal models have provided some directions, but little is known about the specific sensory neurons that undergo changes in such a way as to induce and maintain activation of sensory pain pathways. Our previous studies implicated changes in the Aβ, normally non-nociceptive neurons in activating spinal nociceptive neurons in a cuff-induced animal model of neuropathic pain and the present study was directed specifically at determining any change in excitability of these neurons. Thus, the present study aimed at recording intracellularly from Aβ-fiber dorsal root ganglion (DRG) neurons and determining excitability of the peripheral receptive field, of the cell body and of the dorsal roots.MethodsA peripheral neuropathy was induced in Sprague Dawley rats by inserting two thin polyethylene cuffs around the right sciatic nerve. All animals were confirmed to exhibit tactile hypersensitivity to von Frey filaments three weeks later, before the acute electrophysiological experiments. Under stable intracellular recording conditions neurons were classified functionally on the basis of their response to natural activation of their peripheral receptive field. In addition, conduction velocity of the dorsal roots, configuration of the action potential and rate of adaptation to stimulation were also criteria for classification. Excitability was measured as the threshold to activation of the peripheral receptive field, the response to intracellular injection of depolarizing current into the soma and the response to electrical stimulation of the dorsal roots.ResultsIn control animals mechanical thresholds of all neurons were within normal ranges. Aβ DRG neurons in neuropathic rats demonstrated a mean mechanical threshold to receptive field stimulation that were significantly lower than in control rats, a prolonged discharge following this stimulation, a decreased activation threshold and a greater response to depolarizing current injection into the soma, as well as a longer refractory interval and delayed response to paired pulse electrical stimulation of the dorsal roots.ConclusionsThe present study has demonstrated changes in functionally classified Aβ low threshold and high threshold DRG neurons in a nerve intact animal model of peripheral neuropathy that demonstrates nociceptive responses to normally innocuous cutaneous stimuli, much the same as is observed in humans with neuropathic pain. We demonstrate further that the peripheral receptive fields of these neurons are more excitable, as are the somata. However, the dorsal roots exhibit a decrease in excitability. Thus, if these neurons participate in neuropathic pain this differential change in excitability may have implications in the peripheral drive that induces central sensitization, at least in animal models of peripheral neuropathic pain, and Aβ sensory neurons may thus contribute to allodynia and spontaneous pain following peripheral nerve injury in humans.

Understanding the information and service needs of young adults with chronic pain: perspectives of young adults and their providers.

Objective:To qualitatively explore the information and service needs of young adults (YAs) with chronic pain to inform the development of a web-based chronic pain self-management program. Methods:A convenience sample of YAs (n=17; aged 18 to 29 y) with chronic pain was recruited from 2 adult tertiary care multidisciplinary chronic pain clinics in Ontario. Interdisciplinary health care professionals who had worked in chronic pain for at least 1 year were also recruited from these sites. Five audiotaped focus groups were conducted, 3 for YAs and 2 for health care professionals. Transcribed data were organized into categories that reflected emerging themes. Results:Findings uncovered 4 major themes: (1) pain impact, (2) pain management strategies, (3) barriers to care, and (4) service delivery recommendations. Subthemes were found under each major theme. Pain had an impact on social and emotional realms and role functioning, physical functioning, and future vocational and life goals. Pain management strategies were comprised of psychological, physical, and pharmacological approaches and development of support systems. Barriers to care were revealed at the patient, health care system, and societal levels. Finally, service delivery recommendations were divided into 2 subthemes pertaining to improved services and Internet-based programs. Discussion:Participants unanimously felt that a web-based program would be an acceptable means to help improve access to services and meet the need for more information about chronic pain, strategies to manage pain symptoms, and social support to address the unique developmental needs of YAs.

Changes in Aβ non-nociceptive primary sensory neurons in a rat model of osteoarthritis pain

BackgroundPain is a major debilitating factor in osteoarthritis (OA), yet few mechanism-based therapies are available. To address the need to understand underlying mechanisms the aim of the present study was to determine changes in sensory neurons in an animal model of OA pain.ResultsThe model displayed typical osteoarthritis pathology characterized by cartilage degeneration in the knee joint and also manifested knee pathophysiology (edema and increased vasculature permeability of the joint) and altered nociception of the affected limb (hind paw tenderness and knee articulation-evoked reduction in the tail flick latency). Neurons included in this report innervated regions throughout the entire hind limb. Aβ-fiber low threshold mechanoreceptors exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and slower maximum rising rate, and muscle spindle neurons were the most affected subgroup. Only minor AP configuration changes were observed in either C- or Aδ-fiber nociceptors.ConclusionThus, at one month after induction of the OA model Aβ-fiber low threshold mechanoreceptors but not C- or Aδ-fiber nociceptors had undergone changes in electrophysiological properties. If these changes reflect a change in functional role of these neurons in primary afferent sensory processing, then Aβ-fiber non-nociceptive primary sensory neurons may be involved in the pathogenesis of OA pain. Further, it is important to point out that the patterns of the changes we observed are consistent with observations in models of peripheral neuropathy but not models of peripheral inflammation.

A systematic review of psychometric evaluations of outcome assessments for complex regional pain syndrome.

Purpose: To conduct a systematic review of the quality and extent of psychometric examinations of disease-specific outcome measures for complex regional pain syndrome (CRPS). Methods: Health database searches yielded 23 papers covering 19 assessment instruments. Each article was scored for quality using a 12-item structured tool; data were also extracted for comparison of tool content. Results: Article quality ratings ranged from 25 to 88%. Six of the tools were specific to the upper extremity; 5 for the lower extremities while the remaining 8 were general. Many ‘general’ tools focused on a single construct, such as pain, skin temperature or allodynia. Most psychometric data was based on small studies (mean nu2009=u200933); only one study addressed all relevant issues of reliability, validity and responsiveness. Conclusions: Despite the variety of outcome measurement tools reported for CRPS rehabilitation, large gaps in both comprehensiveness and supporting psychometric evidence remain. Comprehensive, relevant and psychometrically sound tools for monitoring treatment outcomes are needed to address the pain and functional limitations experienced by this population. Implications for Rehabilitation Complex regional pain syndrome (CRPS) is a neurological disorder with signs and symptoms that vary with activity, environment and stress. Although there is no diagnostic test for this syndrome, a need exists for tools to monitor treatment outcomes that address the pain and functional limitations experienced by this population. This review suggests that at present, there is no single comprehensive outcome measure for clinical practice and/or research which has strong supporting psychometric evidence for the evaluation of persons with CRPSAPPENDIX, a scoring sheet and scoring guidelines for critical appraisals for the evaluation of persons with CRPS.

Evaluation of the Iconic Pain Assessment Tool by a heterogeneous group of people in pain.

The Iconic Pain Assessment Tool (IPAT) is a novel web-based instrument for the self-report of pain quality, intensity and location in the form of a permanent diary. Originally designed for people with central poststroke pain, the tool is being adapted for a larger, more diverse patient population. The present study aimed to collect evaluative feedback on the IPAT from a heterogeneous sample of individuals with chronic pain. The specific study aims were to evaluate participant comfort with the tool including enjoyment, ease of use and comfort with the electronic medium; to assess perceived value of the tool for communicating pain quality, intensity and location; to gauge participant intent to share their pain diaries with others and use the tool on a regular basis to track their pain over time; to assess the perceived descriptiveness of current IPAT icons and the numerical rating scale; and to identify strengths and weaknesses of the tool to refine the existing prototype. Written and verbal feedback from individuals with a variety of chronic pain conditions (n=23) were collected in the context of these objectives. Overall, the IPAT was positively endorsed by this heterogeneous sample of people in pain. The authors concluded that the IPAT is a user-friendly instrument that has the potential to help people express, document and share their personal experience with chronic pain.