Biologics: the next-generation therapeutics for analgesia?

There is a huge unmet need for novel medicines for the treatment of chronic pain. In this article, we briefly examine some of the issues associated with traditional approaches to the treatment of these conditions. We go on to present some of the current evidence for three of the most advanced approaches to the treatment of pain using a biological approach and briefly review some of the future trends that may lead to better treatments for this debilitating condition.

Biologic drugs for analgesia: redefining the opportunity.

Chronic pain conditions present a huge burden on modern society. Both inflammatory and neuropathic pain are poorly treated in man; the majority of patients do not benefit from adequate pain relief, and side effects of currently used treatments are common. Discovery and development of novel therapies remains an imperative, but the ability to genuinely test the efficacy of novel therapies is often limited by effects at targets other than intended, particularly with novel small molecule approaches. Approaches which limit these off-target activities, and thus avoid the commonest cause of terminating development of new therapeutics may provide a greater ability to genuinely test targets of choice clinically, and here, biologic therapeutics provide such an opportunity; in the major class of biologic therapies, monoclonal antibodies, inherent exquisite selectivity is intrinsic to their nature. Antibody therapeutics have been developed successfully in the immunology and cancer fields, and recent progress in analgesia suggests that these therapeutics may transform treatment paradigms in a similar manner to that observed within, for example, the rheumatoid arthritis space. In addition, opportunities with other biologic approaches, such as peptides, further broadens the potential to bring forward genuinely novel approaches to pain. In this review, the current status of biologic therapies, as well as future opportunities are reviewed.

The role of P2X7 in pain and inflammation.

The P2X 7purinoceptor is unique amongst the P2X receptor family in that its activation is able to stimulate the release of mature, biologically active interleukin-1beta (IL-1ß), as well as a variety of other proinflammatory cytokines. Coupled with the predominate localisation of this receptor to immunocytes of haemopoetic origin, this receptor is an obvious candidate to play a major and pivotal role in processes of pain and inflammation. Using genetically modified animals that lack the P2X7 receptor, several investigators have shown that these mice do indeed demonstrate a blunted inflammatory response, and fail to develop pain following both inflammatory and neuropathic insult. These animals also show altered cytokine production in response to inflammatory stimulus, which is far broader than merely modulation of IL-1ß release. In this short article, we review the role of the P2X7 receptor in modulating the release of cytokines and other mediators, and discuss the findings made from P2X7 receptor-deficient animals. As well as highlighting outstanding questions regarding this intriguing receptor, we also speculate as to the potential therapeutic benefit of P2X7 receptor modulation.

Transgenic models of pain: a brief review.

Early validation of novel targets for the treatment of pain remains a key challenge, despite the recent technological advances which aid more rapid generation of pharmacological tools and molecular techniques that allow in vivo manipulation of gene transcription. Use of genetically modified animals, particularly 'knockouts', has been critical in evaluating the function of targets for which pharmacological manipulation has proved difficult. This review discusses recent findings from such investigations for three of the larger target classes, and highlights the relative merits and drawbacks of this methodology compared with other methods for the functional investigation of the role of individual molecular targets in pain.

Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain.

The P2X(7) purinoceptor is a ligand-gated cation channel, expressed predominantly by cells of immune origin, with a unique phenotype which includes release of biologically active inflammatory cytokine, interleukin (IL)-1beta following activation, and unique ion channel biophysics observed only in this receptor family. Here we demonstrate that in mice lacking this receptor, inflammatory (in an adjuvant-induced model) and neuropathic (in a partial nerve ligation model) hypersensitivity is completely absent to both mechanical and thermal stimuli, whilst normal nociceptive processing is preserved. The knockout animals were unimpaired in their ability to produce mRNA for pro-IL-1beta, and cytometric analysis of paw and systemic cytokines from knockout and wild-type animals following adjuvant insult suggests a selective effect of the gene deletion on release of IL-1beta and IL-10, with systemic reductions in adjuvant-induced increases in IL-6 and MCP-1. In addition, we show that this receptor is upregulated in human dorsal root ganglia and injured nerves obtained from chronic neuropathic pain patients. We hypothesise that the P2X(7) receptor, via regulation of mature IL-1beta production, plays a common upstream transductional role in the development of pain of neuropathic and inflammatory origin. Drugs which block this target may have the potential to deliver broad-spectrum analgesia.

The cyclooxygenase-2 inhibitor GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine] is effective in animal models of neuropathic pain and central sensitization.

The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for rofecoxib and 6.6 mg/kg p.o. for celecoxib. However, in contrast to celecoxib (5 mg/kg p.o. b.i.d.) and rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect, GW406381X (5 mg/kg p.o. b.i.d.) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitization, when given intrathecally (ED(50) = 0.07 mug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including central nervous system penetration, enzyme kinetics, and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitization, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared with celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.