Drug Discovery and Development for Pain

Two decades ago, systemic drugs indicated for pain belonged roughly to three mechanistic classes: the opioids, the nonselective NSAIDs, and the anticonvulsants, the latter class represented by a single member, carbamazepine. As of this writing, there are approximately 10 classes of drugs approved for use in the management of pain in the United States and Canada. Recent additions to the pharmacopoeia for pain exemplify two significantly differing pathways for bringing new pain therapies to market. On the one hand, there are drugs that have been in clinical use for some time for other indications, which have been shown to have analgesic efficacy and subsequently have obtained additional label indications for the treatment of pain. Examples in this category include the alpha-2 adrenoreceptor agonist clonidine (launched as an antihypertensive in 1966; gained approval for epidural use in the treatment of cancer pain 1996), and the anticonvulsant gabapentin (launched as an anticonvulsant 1994; gained approval for neuropathic pain in 2002). A number of additional marketed drugs have repeatedly demonstrated therapeutic efficacy in pain states in controlled studies but lack specific label approval for this indication. For example, randomized, controlled studies have demonstrated the utility of older tricyclic antidepressants including amitriptyline, nortriptyline, and desipramine in chronic pain states; due to the preponderance of supportive evidence these drugs are considered useful pain therapeutics. Ongoing advances in the understanding of pain mechanisms continue to reveal opportunities for the creative use of drugs of known pharmacology. In addition, many older, marketed drugs reveal a surprising richness of pharmacology when studied using new methods. Due to their potential for benefit, and also due in no small part to the lengthy and complex process required for the development and regulatory approval of novel drugs, there are many obvious advantages to the study of approved medications for the treatment of pain. The ability to conduct clinical trials with a substance that is already approved for use in humans provides for immediate testing of a hypothesis. Furthermore, since approved drugs have by definition already amassed the requisite preclinical and clinical safety data, positive results from such trials lead to a much shorter path to new regulatory approval, and thus the considerable costs of years of study involved in novel compound discovery and development are avoided. There are, however, limitations to this approach. Existing drugs may not have the ideal pharmacological or pharmacokinetic properties required. In addition, while the cost outlay of repurposing approved drugs is far less than that of inventing new ones, the retur on investment may be poor. Market protection for drugs with older patents may be limited, and from a purely business standpoint, cost analyses of investing in new research for such older drugs may be unfavorable. In addition, as safety regulation becomes more stringent, pharmaceutical companies may be reluctant to assume safety liabilities of drugs that were originally approved under less rigorous requirements. On the other hand, recent advances in research have resulted in the development of entirely novel classes of drugs, specifically developed as analgesics and brought forward with pain as an initial indication. These include COX2-selective inhibitors (celecoxib launched 1999 for pain and inflammation), the N-type calcium channel inhibitor ziconotide (launched 2005), the triptan class of serotonin receptor subtype 1B/D agonists (sumatriptan launched early 1990s), and newer cannabinoids such as Sativex, launched in Canada 2005 for the treatment of pain and spasticity due to multiple sclerosis. Because of the lengthy and complex evaluation required to bring a compound to market, the failure rate of new compounds is extremely high, as are the costs of development. The current estimate of the expenditure required to bring a new compound to market hovers near US $1 billion. Hundreds of thousands of compounds may be screened in order to identify one or two compounds that are considered suitable clinical candidates. Industry estimates are that these clinical candidates have about a 90% chance of failure during the most costly stage of evaluation, clinical trials. In general, across therapeutic areas, reasons for failure include disappointing pharmacokinetic properties in humans, unacceptable clinical safety profiles, and lack of clinical efficacy. Compounds may also fail to reach the marketplace due to other advances in the therapeutic field (for example, the development of selective serotonin reuptake inhibitors supplanting the tricyclic antidepressants) or commercial reasons, such as the inability of a company to support an orphan drug program. Nevertheless, drug discovery for pain is an exciting, fast-paced, and rewarding field. Both the investigation of the analgesic effects of marketed drugs and the pioneering of novel drug classes are active areas of research and development: a survey of industry pipeline databases reveals more than 25 different mechanistic classes of compounds in various stages of evaluation.