Bruce L. Kidd

Towards a mechanism-based classification of pain?

It is self evident that the recent explosive growth in our understanding of the molecular, cellular and system’s mechanisms responsible for nociception and pain has important implications for the clinical diagnosis and treatment of pain. A small group of independent basic scientists and clinicians met in New York in January 1998, for a wide ranging discussion on the possible need for and implications of a mechanism-based classification of pain. The group believed that acceptance of a mechanism-based classification could have profound implications: drugs may be developed which target distinct mechanisms, basic scientists may have new guidelines for experimental design, and clinicians may be eventually armed with more reliable and valid diagnostic tools for treatment and clinical investigation. Furthermore, a mechanism-based classification for clinical syndromes might generate testable hypotheses for selecting treatments which interact with specific mechanisms. We wish to initiate a wide debate on this important topic by highlighting what we consider to be some of the key issues. In general, taxonomies can be either natural or artificial. Examples of each, respectively, are the division of objects into animate or inanimate groups (which reflects order in nature) and a telephone book (which is merely a conventional way of listing peoples’ numbers and addresses). Natural taxonomies are based on theoretical ideas of how the world is organized. Artificial taxonomies provide convenient or practical methods for organizing the world. Consequently they do not easily facilitate the development of new ideas. A mechanism-based classification of pain requires a conceptual understanding of organization in nature, and would, therefore, set a framework for scientific development. Current methods of classifying pain have, we believe, a number of major limitations. Pain syndromes are identified by parts of the body, duration, and causative agent. We believe that an anatomical-based classification of pain is limiting because the innervation of distinct anatomical regions is often analogous, bearing in mind differences of target organ innervated (e.g. skin vs. viscera), length of axon, myelination, etc. To the extent that universal mechanisms can be identified, anatomical differences should be disregarded in favor of mechanisms that apply to all parts of the body. The acute/chronic dichotomy is also not helpful. Acute and chronic do not readily differentiate mechanisms. The benign/malignant dichotomy too has no mechanistic basis for pain, although it will influence treatment strategies. Greater care needs also to be taken with the definition of terms such as allodynia and hyperalgesia. Both terms are a description of clinical symptoms and do not imply a mechanism. Allodynia (pain evoked by normally non-painful stimuli) is often used in the clinical context to refer to Ab-fiber mediated brush-evoked mechanical pain or an altered processing of sensory information in the CNS. However, there are several other distinct types of mechanical hypersensitivity that do not involve A b fibers and probably no significant central reorganization, but which present as pain evoked by commonly non-painful stimuli. Reduction in threshold is not, therefore, useful by itself, for a mechanistic classification. From a practical perspective, clinicians use classification systems to predict treatment responses as well as prognosis and to search for risk factors and morbidities. Ultimately any classification system must be judged on its utility for clinical practice and research. The most powerful systems could be organized by mechanism, by disease or etiology. In the neuropathic disease category, at least, the disease classification system was considered by the group to fail to Pain 77 (1998) 227–229

Pain related behaviour in two models of osteoarthritis in the rat knee

Abstract Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predominant clinical feature, yet therapy is ineffective for many patients. While there are considerable insights into the mechanisms underlying tissue remodelling, there is poor understanding of the link between disease pathology and pain. This is in part owing to the lack of animal models that combine both osteoarthritic tissue remodelling and pain. Here, we provide an analysis of pain related behaviours in two models of OA in the rat: partial medial meniscectomy and iodoacetate injection. Histological studies demonstrated that in both models, progressive osteoarthritic joint pathology developed over the course of the next 28 days. In the ipsilateral hind limb in both models, changes in the percentage bodyweight borne were small, whereas marked mechanical hyperalgesia and tactile allodynia were seen. The responses in the iodoacetate treated animals were generally more robust, and these animals were tested for pharmacological reversal of pain related behaviour. Morphine was able to attenuate hyperalgesia 3, 14 and 28 days after OA induction, and reversed allodynia at days 14 and 28, providing evidence that this behaviour was pain related. Diclofenac and paracetamol were effective 3 days after arthritic induction only, coinciding with a measurable swelling of the knee. Gabapentin varied in its ability to reverse both hyperalgesia and allodynia. The iodoacetate model provides a basis for studies on the mechanisms of pain in OA, and for development of novel therapeutic analgesics.Abbreviations: OA: osteoarthritis; DRGs: dorsal root ganglia; NSAIDs: non‐steroidal anti‐inflammatory drugs; PWT: paw withdrawal thresholds; p.o.: orally; s.c.: sub cutaneously.

A rat model of bone cancer pain

&NA; This study describes the first known model of bone cancer pain in the rat. Sprague–Dawley rats receiving intra‐tibial injections of syngeneic MRMT‐1 rat mammary gland carcinoma cells developed behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology. Intra‐tibial injections of 3×103 or 3×104 syngeneic MRMT‐1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10–14 after inoculation of 3×103 MRMT‐1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However, tartarate‐resistant acid phosphatase staining revealed a large number of polykariotic cells, resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat‐killed MRMT‐1 cells. Intra‐tibial injections of 3×103 or 3×104 MRMT‐1 cells, heat‐killed cells or vehicle did not show changes in body weight and core temperature over 19–20 days. The general activity of animals after injection with live or heat‐killed MRMT‐1 cells was higher than that of the control group, however, the activity of the MRMT‐1 treated group declined during the progress of the disease. Rats receiving intra‐tibial injections of MRMT‐1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12–14 or 10–12 following injection of 3×103 or 3×104 cells, respectively. These symptoms were not observed in rats receiving heat‐killed cells or vehicle. Behavioural data suggest a reasonable time window for evaluation of anti‐nociceptive agents between day 14 and 20 after cancer cell inoculation in this model. Acute treatment with morphine (1–3 mg/kg, subcutanously (s.c.)) produced a dose‐dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra‐tibial injections of 3×103 MRMT‐1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10–30 mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3×103 MRMT‐1 cells. Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes. In summary, the induction of bone cancer in the rat by the syngeneic MRMT‐1 mammary tumour cell line provides a valid pre‐clinical model for pain associated with bone metastases. Significant mechanical hyperalgesia and allodynia develops in association with the progression of the tumour in the bone marrow cavity, while the general condition of the animal remains satisfactory. While acute treatment with morphine has some analgesic effect on hind limb sparing the selective COX‐2 inhibitor, celebrex, has no influence on the pain‐related behavioural changes in this model.

Osteoarthritis and joint pain.

Most people will experience musculoskeletal pain at some point in their lives with more than one in five suffering from persistent back or joint pain. Significantly, such pain is associated with worse functional outcomes and poorer quality of life when compared to a range of other chronic conditions (Sprangers et al., 2000). Osteoarthritis (OA) is the most common of the articular disorders and is frequently cited as the leading cause of persistent musculoskeletal pain although the relationship between symptoms and underlying pathology is far from straightforward. This review examines some of the factors underlying pain in OA and outlines implications for present and future therapy.

The differential contribution of tumour necrosis factor to thermal and mechanical hyperalgesia during chronic inflammation

Therapies directed against tumour necrosis factor (TNF) are effective for the treatment of rheumatoid arthritis and reduce pain scores in this condition. In this study, we sought to explore mechanisms by which TNF contributes to inflammatory pain in an experimental model of arthritis. The effects of an anti-TNF agent, etanercept, on behavioural pain responses arising from rat monoarthritis induced by complete Freunds adjuvant were assessed and compared with expression of TNF receptors (TNFRs) by dorsal root ganglion (DRG) cells at corresponding time points. Etanercept had no effect on evoked pain responses in normal animals but exerted a differential effect on the thermal and mechanical hyperalgesia associated with rat arthritis induced by complete Freunds adjuvant (CFA). Joint inflammation was associated with increased TNFR1 and TNFR2 expression on DRG cells, which was maintained throughout the time course of the model. TNFR1 expression was increased in neuronal cells of the DRG bilaterally after arthritis induction. In contrast, TNFR2 expression occurred exclusively on non-neuronal cells of the macrophage–monocyte lineage, with cell numbers increasing in a TNF-dependent fashion during CFA-induced arthritis. A strong correlation was observed between numbers of macrophages and the development of mechanical hyperalgesia in CFA-induced arthritis. These results highlight the potential for TNF to play a vital role in inflammatory hyperalgesia, both by a direct action on neurons via TNFR1 and by facilitating the accumulation of macrophages in the DRG via a TNFR2-mediated pathway.

Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain.

&NA; Inoculation of syngeneic MRMT‐1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 &mgr;g/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase‐positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX‐2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti‐hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti‐metastatic and bone preserving therapeutic effects, is an anti‐nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.

Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a prospective placebo controlled double blind trial

OBJECTIVE Vitamin E, the most potent naturally occurring lipid soluble antioxidant has been suggested to possess both anti-inflammatory and analgesic activity in humans. This double blind and randomised study used a broad spectrum of clinical and laboratory parameters to investigate whether there was any additional anti-inflammatory or analgesic effects, or both, of orally administered α-tocopherol in rheumatoid arthritis patients who were already receiving anti-rheumatic drugs. METHODS Forty two patients were enrolled and treated with α-tocopherol (n=20) at a dose of 600 mg twice a day (2 × 2 capsules) or with placebo (n=22) for 12 weeks. The following parameters were measured: (1) Three clinical indices of inflammation—the Ritchie articular index, the duration of morning stiffness, and the number of swollen joints; (2) three measures of pain—pain in the morning, pain in the evening, and pain after chosen activity; (3) haematological and biochemical measures of inflammatory activity; (4) assays for the oxidative modification of proteins and lipids. RESULTS All laboratory measures of inflammatory activity and oxidative modification were unchanged. Furthermore, the clinical indices of inflammation were not influenced by the treatment. However, the pain parameters were significantly decreased after vitamin E treatment when compared with placebo. CONCLUSION The results provide preliminary evidence that vitamin E may exert a small but significant analgesic activity independent of a peripheral anti-inflammatory effect, but which complements standard anti-inflammatory treatment.

Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis

Abstract Rheumatoid arthritis (RA) is characterised by pain and tenderness not only over inflamed or damaged joints, but also over apparently normal tissues. Experimental models suggest that these features result from changes of sensitivity within both peripheral and central neurones, but direct evidence from human disease is lacking. At present, most clinical studies have evaluated overall pain experience rather than activity within components of the nociceptive pathway. Therefore, the aim of this study was to assess the use of a capsaicin‐based technique to quantify changes of neuronal sensitivity in patients with RA. First 20 &mgr;l of capsaicin in solution (0.03 mg/ml) was applied topically for 30 min to apparently normal skin on the forearm of control subjects and patients with RA. The subsequent development of mechanical hyperalgesia to pinprick stimuli was then measured at various time points using a 74.4‐mN von Frey hair. The relationship between the area of hyperalgesia and a number of clinical measures was determined. Capsaicin‐induced mechanical hyperalgesia was found to decline with age in normal subjects (r=0.47, P<0.01). The development of hyperalgesia had a similar time course in normal subjects and patients with RA. The maximum area of hyperalgesia, however, was substantially larger in 35 RA patients; 254.3±20.7 cm2, compared with 35 normal controls; 109±7.5 cm2 (P<0.001). An association was apparent between hyperalgesic area and a composite score of joint tenderness (r=0.47, P<0.01), but not with overall pain score or a systemic marker of inflammation. These results provide evidence for enhanced sensitisation of a population of sensory fibres in RA. Peripheral sensory activity over the forearms of rheumatoid patients has previously been shown to be normal and the results suggest the presence of enhanced central mechanisms in this disorder. The correlation between capsaicin‐induced hyperalgesia and joint tenderness in the RA patients implies that joint symptoms arise partially as a result of central, and not exclusively peripheral, factors. The study supports the use of capsaicin‐based techniques to explore nociceptive mechanisms in clinical disorders characterised by chronic pain.

Monoarthritis in the rat knee induces bilateral and time-dependent changes in substance P and calcitonin gene-related peptide immunoreactivity in the spinal cord.

Bilateral changes in the spinal cord and dorsal root ganglion content of the sensory peptides substance P and calcitonin gene-related peptide have been previously reported in animal models of arthritis which affect many joints within the body. The central nervous system has been implicated in the symmetry of joint involvement in human rheumatoid arthritis. We aimed to determine whether unilateral inflammation of the knee joint can also induce bilateral changes in the spinal cord. We have induced a monoarthritis in the knee joint of the rat and used quantitative immunocytochemistry to look at changes of these peptides in the dorsal horn of the spinal cord and the dorsal root ganglia. Furthermore we have examined the responses during the acute (three days) and the chronic (21 days) phases of the model. The data show that in the acute phase of the monoarthritis there is both an ipsilateral and contralateral response which increases the immunoreactive substance P and calcitonin gene-related peptide in the L4 level of the dorsal horn of the spinal cord. In the chronic phase of the monoarthritis, the contralateral side of the dorsal horn returned to control values whilst the ipsilateral side showed reduced amounts of immunoreactive substance P and calcitonin gene-related peptide compared to controls. We propose that the acute response, at three days, to unilateral inflammation is appropriate and has evolved to protect an organism against the original insult ipsilaterally, and the possibility of subsequent insult contralaterally.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of bradykinin B1 receptors in the maintenance of intra-articular plasma extravasation in chronic antigen-induced arthritis.

1 The role of bradykinin B1 and B2 receptors in bradykinin‐ and des‐Arg9‐bradykinin‐induced plasma extravasation in normal and inflamed rat knee joints was investigated by use of an antigen‐induced model of chronic arthritis. A modification of an Evans blue extraction technique allowed the unstimulated (basal) plasma extravasation to be assessed in this model. The contributions of bradykinin B1 and B2 receptors towards basal synovial plasma extravasation were determined. 2 In normal knees, intra‐articular injection of bradykinin (BK) induced plasma extravasation in a potent, dose‐dependent manner with a threshold of 0.01 nmol and an ED50 of 0.1 nmol. In day 5 arthritic knees, basal plasma extravasation was substantially enhanced. Lower doses of BK had no demonstrable effect and increases above basal extravasation were first observed at 0.1 nmol. Thereafter the dose‐response mirrored the response in normal knees and the maximal response was unaltered. 3 The B1 agonist, des‐Arg9‐BK, induced slight but significant plasma extravasation in normal knees but was less potent than bradykinin. This response was inhibited by the Bi receptor antagonist, des‐Arg9, [Leu8]‐BK. Lower doses of des‐Arg9‐BK bradykinin did not significantly increase basal extravasation in day 5 arthritic knees but, in contrast to BK, the maximal response was significantly enhanced. 4 The B2 antagonist, Hoe 140, inhibited BK‐induced plasma extravasation in normal joints over a dose‐range of 0.1‐1.0 nmol but was relatively inactive in day 5 inflamed knees. The B1 receptor antagonist, des‐Arg9, [Leu8]‐BK, was relatively inactive in normal joints but showed increased potency against BK‐induced plasma extravasation in day 5 arthritic joints. 5 Hoe 140 and des‐Arg9, [Leu8]‐BK both inhibited basal extravasation in arthritic joints on days 1 and 5 post‐challenge in a dose‐dependent fashion. Whilst Hoe 140 was the more potent inhibitor on day 1, it was less potent than des‐Arg9, [Leu8]‐BK on day 5. 6 Although the majority of responses to BK in normal tissue are mediated via B2 receptors, a small population of B1 receptors may exist in normal joint tissues. The data presented in this study suggest an evolving role for Bx receptors in the mediation of plasma extravasation in inflamed joint tissues. A role for BK antagonists in the treatment of arthritis is also suggested.