The Nature and Origins of Pain Therapeutics

Pain comes in many varieties, some quite temporary, some that pass with healing, and others that stay on for life. Many victims of terminal illness have to deal not only with their imminent demise, but with intractable pain that adds misery to their last days. A variety of drugs to deal with pain have been handed down to us, and some excellent new ones have been added along the way. They do best in alleviating the temporary pain that comes when tissue damage and inflammation set off pain signals in the nervous system. They do less well with the various sorts of chronic pain that settle in for a long stay, and they do least well with neuropathic pain resulting from the nervous system’s maladaptive reorganizations following nerve injury.

Pain can be especially challenging for healthcare providers who have little or no means for objective measurement of a patient’s pain. To a large extent pain is subjective, relying on the patient’s perceptions and expectations, which can vary greatly from one patient to another. In the absence of objective pathological findings, the physician can rely on little but the patient’s assessment of his or her pain, and too often (decreasingly so) the practitioner opts for undertreatment on the assumption that the patient is exaggerating or malingering. In dealing with extreme pain, even the most caring and cooperative physician is often faced with Hobson’s choice of undertreating the patient or causing more harm than good.

Pain therapeutics is clearly an area greatly in need of improvement. The healthcare provider side of the equation has shown significant improvement during the past decade, with large increases in the number of pain specialists practicing and much greater willingness to treat pain aggressively when necessary. Pain management is no longer the sole province of either the primary care physician or non-pain specialist. There is growing recognition that pain is a multifaceted problem requiring inputs from multiple perspectives. The growth of pain clinics utilizing interdisciplinary provider teams, together with both mainstream and alternative approaches to pain management, indicates the adoption of new medical paradigms in the field. The emergence and rise of pain medicine as a distinct medical specialty and the increasing inclusion of pain education and training in medical school curricula are positive signs.

Growing public and professional awareness of pain-related issues has also stimulated pharmaceutical and biotechnology companies to move pain therapeutics higher in their awareness and activities as they come to appreciate the scale of unmet needs in the field. Pain therapeutics is also benefiting from rapid progress in the methodologies of neurological research and the addition of genomic-era technologies to the research armamentarium. Pharmaceutical and biotechnology companies have recognized this re-emergent high-potential business opportunity and are taking advantage of new basic understandings of pain physiology and the identification of new target entities to undertake the development of new drugs targeted at particular categories of pain. While pain remains a difficult subject both for patients and providers, there is ample room for optimism in the new millennium.

The history of pain is tied closely to the evolution of analgesic pharmacology. Early pain drugs came from plants—e.g., opium from the poppy, belladonna from deadly nightshade, and marijuana from Cannabis indica. An early anesthetic device, the soporific sponge used in the Middle Ages, was made by impregnating a sponge with extracts of opium, nightshade, hemlock, mandragora, ivy, and lettuce seed. The wetted sponge was applied to the nostrils until the patient fell asleep and surgery could be performed.

As today, people bought over-the-counter pain medications, most of which contained alcohol or opium. Morphine, which was isolated from opium in 1806, was often injected by physicians for severe or postoperative pain. By the end of the 19th century, German chemical companies had introduced new compounds—including salicylates and acetanilide—for relief of mild-to-moderate pain. Salicylates, however, tended to cause adverse gastrointestinal side effects. Bayer’s 1899 introduction of the well-tolerated acetylsalicylic acid (aspirin) marked a major milestone in analgesic history. Within a few years, aspirin had become the world’s best-selling drug.

Knowledge of the pathophysiology of pain can be traced to the work of Charles Bell and Francois Magendie in the early 19th century, who discovered that posterior roots of spinal nerves responded to sensations, while anterior roots were associated with motor responses. This research led to the idea that pain sensations had their own neural pathways. The concept was fleshed out by others during the rest of the century with the elaboration of pain pathways in the spinal cord, the discovery of pain-related locations in the brain, and the identification of “pain spots” on the skin.

A key point in the history of pain research came in 1898 when Sir Charles Scott Sherrington proposed the concept of nociception, i.e., the notion that pain is an evolved response to a potentially harmful (“noxious”) stimulus. He put forth the notion that the main function of the nervous system was the integration of various activities of the organism. Although Sherrington emphasized integration and competition of stimuli for nerve pathways, early 20th century neurophysiologists came to accept a “telephone exchange” or “specificity” pain model in which peripheral receptors link to spinal neurons, which link to the brain, thus producing a motor response.

Two pain syndromes—phantom limb pain and causalgia—could not readily be explained in terms of the above “one-way” model. Phantom pain syndrome caused some amputees to experience pain from a missing limb, and causalgia resulted in pain felt, after an injury had healed, at some body site distant from that of the original wound. The use of localized nerve blocks or surgical severing of nerve pathways was often ineffective in dealing with either kind of pain.

The American neurologist, S. Weir Mitchell, wrote in 1872:

“Perhaps few persons who are not physicians can realize the influence which long-continued and unendurable pain may have on body and mind . . . Under such torments the temper changes, the most amiable grow irritable, the bravest soldier becomes a coward, and the strongest man is scarcely less nervous that the most hysterical girl. Nothing can better illustrate the extent to which these statements may be true than the cases of burning pain, or, as I prefer to term it, causalgia, the most terrible of all tortures which a nerve wound may inflict.”1

William K. Livingston, the Harvard-trained physician who wrote Pain Mechanisms in 1943, felt that the prevalent pain mechanism model was insufficient. He believed that pain is a subjective and individual sensory experience, which can exceed its protective function and become destructive. He felt that chronic irritation of sensory nerves could cause major and even permanent changes resulting in chronic pain.

Although experimental work in neurophysiology continued to provide support for the specificity pain model through 1940s, several alternatives were proposed. None became widely accepted until 1965 when a Canadian psychologist, Ronald Melzack, and a British physiologist, Patrick Wall, generated the gate control theory of pain.2 The theory postulated a gating mechanism in the spinal cord that closed upon normal stimulation of fast-conducting sensory nerve fibers responsive to touch, but opened when slow-conducting pain-related nerve fibers transmitted a high volume and intensity of sensory signals. Melzack and Wall also believed that the gate could be closed through countering these signals by renewed stimulation of the large fibers. Although the gate control model has been significantly revised since 1965, it successfully integrated many experimental and clinical observations, and its new perspective inspired the work of a new generation of pain researchers. The concept of modulation of pain perception within the nervous system remains a central element in pain research.

Another great milestone in pain research came in 1971 from the laboratory of John C. Liebeskind at the University of California, Los Angeles, with the discovery that stimulation of the midbrain area called the PAG (periaqueductal gray) produced pain in animals, but reducing the stimulation produced analgesia. Liebeskind suggested that the effect was similar to the analgesia produced by opiates, and his group went on to show the effect was blocked by the opioid antagonist naloxone. This work led to the later discovery of the opiate receptor in 1973 by Lars Terenius of Uppsala University and its unequivocal measurement by Solomon Snyder and Candace Pert at Johns Hopkins University that same year. The first endogenous opioid, enkephalin, was discovered and characterized in 1975 by Hans Kosterlitz and his coworkers at the University of Aberdeen, Scotland. And so was born modern pain pharmacology.

The Scope of the Pain Problem

The number of individuals adversely affected by pain in its many manifestations is impressively large. Several estimates are presented to provide some perspective on the scope of the problem and attendant market opportunities for companies active in the field:

·        Pain is a condition that afflicts approximately 86 million Americans, causing losses to US business and industry of about $90 billion (American Chronic Pain Association, 2001)

·        One in three American adults loses more than 20 hours of sleep each month due to pain (American Chronic Pain Association, 2001)

·        One in six Americans suffers from arthritis, and 26 million of those are women (American Pain Association, 2001)

·        Back pain is the leading cause of disability in Americans under 45 years old; more than 26 million Americans between the ages of 20 and 64 will have back pain during their lifetime (American Pain Association, 2001)

·        Migraine headaches afflict about 28 million people aged 12 and older (about 13% of the population) in the US. More than half of these individuals have never received a physician diagnosis of migraine and most are not receiving the most appropriate treatment (National Headache Foundation, 2001)

A major chronic pain survey in Australia3 involved more than 17,000 interviews with subjects randomly chosen by telephone number. Chronic pain was reported by 17.1% of males and 20.0% of females. Eleven percent of males and 13.5% of females reported some degree of impairment of daily activities associated with their pain. Although the incidence of pain clearly increased with age, younger respondents with chronic pain were proportionately most likely to report that pain interfered with their activities (84.3% of females and 75.9% of males). There were strong associations between having chronic pain and receiving disability benefits (p < 0.001) and being unemployed due to health reasons (p < 0.001).

References

1. Mitchell, S.W., Injuries of Nerves and Their Consequences, (Philadelphia: J.B. Lippincott, 1872).

2. Melzack, R., and Wall, P., “Pain Mechanisms: A New Theory,” Science 150:171–9, 1965.

3. Blyth, F.M., et al., “Chronic Pain in Australia: A Prevalence Study,” Pain 89:127–34, 2001.

This article is adapted from the Introduction to D&MD Report’s “Pain Therapeutics: A New Era of Research Innovations and Commercial Opportunities,” by Ken Rubenstein, PhD. For more information on this market analysis report, including how to order a copy, please click here.

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