New Gains for Pain

Even with $20.6 billion in 2004 estimated prescription sales, pain management remains one of the most widely researched yet undertreated therapeutic areas. That leaves plenty of room for growth, and industry experts predict that revenue from pain-management therapeutics will reach almost $29.8 billion by 2008.

Much of that growth will be fueled by an aging global population—suffering from arthritis, cancer, diabetic neuropathy, and postoperative pain. But those patients—and, in fact, most patients—will receive more palliative care than in the past because of society's changing attitude toward pain management.

"In the old school of thinking, patients were hesitant to ask for more analgesics," says Carol Ammon, CEO of Endo Pharmaceuticals, a specialty pharma with a focus on pain products. "Patients were socialized to accept a certain amount of pain. I think a lot of that has gone out the window now. Patients realize that they can appropriately have their pain treated and that they are not bad patients for asking to have it treated."

The biggest growth potential is in the United States, which had sales of $12.3 billion in 2003. That figure should balloon to an estimated $21.8 billion in 2008. Leading players—including Pfizer, Purdue, Johnson & Johnson, Merck, and Novartis—account for approximately 60 percent of the US pain-management market. Yet because there are still unmet needs in pain management, there is room for many other companies, such as Abbott Labs, Durect, Eli Lilly, Endo, and Forest Labs, to gain market share.

Global Market Growth, Global Market Share

Defined and Indicated

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience in association with actual or potential tissue damage, or described in terms of such damage." For patients, it's just a big hurt, but for doctors and pharma companies seeking FDA indications, pain is typically categorized by duration: acute (postoperative pain) or chronic (low-back pain). Chronic pain is defined as pain that lasts more than six months, and acute pain is a condition experienced for less than six months.

Another category, neuropathic pain, is usually chronic and is caused by lesions in the peripheral or central nervous system. Various medical conditions and external factors, including diabetes, herpes zoster (shingles), cancer, exposure to toxic substances (including chemotherapy), alcoholism, stroke, HIV, and multiple sclerosis can all lead to neuropathic pain.

Breakthrough pain refers to intermittent flares experienced by patients who are already on a fixed, around-the-clock pain therapy regimen. An episode can last anywhere from just a few seconds to several hours and can be triggered by a specific activity (coughing or moving) or may start unexpectedly and for no reason.

Available therapeutics for pain can be classified in three categories: nonopioids, opioids, and adjuvants. The nonopioids include nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Tylenol). NSAIDs constitute the majority of this category; they range from traditional, over-the-counter pain relievers (including aspirin, ibuprofen, and naproxen) to newer, prescription COX-2 inhibitors (including celecoxib, rofecoxib, and valdecoxib).

NSAIDs act by inhibiting the conversion of arachindonic acid to prostaglandin, a substance produced by the body that plays a role in inflammation and pain. Although traditional NSAIDs are considered relatively safe, COX-2 inhibitors have fallen under increased scrutiny following Merck's voluntary withdrawal of Vioxx (rofecoxib), because of research showing increased risks of heart attacks and strokes.

Although nonopioids are generally used for mild to moderate pain, opioids— such as morphine, fentanyl, hydrocodone, and oxycodone—are used to manage moderate to severe pain and chronic pain. Opioids bind to opiate receptors that are located in the central nervous system and decrease the transmission of nociceptive input (pain caused by irritation or injury) —reducing the perception of pain in the brain.

Adjuvants include antidepressants, anticonvulsants, and other therapeutics that are used off-label or in combination with nonopioid and opioid therapies. (See "Off-Label Controversy,".)

Off-Label Controversy

Neuropathic Need

Worldwide, there are few options that effectively address neuropathic pain, with only eight drugs approved for such conditions. (See "Global Neuropathic Pain Growth" and "Neuropathic Market Share,".) Only three are marketed worldwide: Lidoderm (lidocaine patch), a topical analgesic, and Neurontin (gabapentin) and Tegretol (carbamazepine), both of which are anticonvulsants with undefined mechanisms of action. Tegretol is a rarely prescribed drug indicated for trigeminal neuralgia (a rare form of neuropathic pain), leaving Pfizer's Neurontin and Endo's Lidoderm as the only substantially viable options for most US patients.

Global Neuropathic Growth, Neuropathic Market Share

FDA, however, has approved those two drugs for the limited indication of neuropathic pain associated with herpes zoster (postherpetic neuralgia), which means most US prescriptions are off-label. In Europe, Neurontin is indicated for the broader category of neuropathic pain, allowing Pfizer to legally market it there for various types of painful neuropathy.

Hartaj Singh, managing consulting at Navigant Consulting, explains why FDA is so strict. "It is hard to design clinical trials around neuropathic pain, as clinical endpoints for neuropathic pain are not well defined and are difficult to measure, with the exception of postherpetic neuralgia." But until FDA becomes more lenient in the indications granted to neuropathic pain treatments, growth in the US market will be somewhat hindered.

Fortunately, there are products in the pipeline that hold promise for the near future. New drugs entering the pain market include four products under development specifically for neuropathic pain: Pfizer's Lyrica (pregabalin), Elan's Prialt (ziconotide), GW Pharmaceuticals' Sativex (cannabis extract), and GSK's Lamictal (lamotrigine), which, like Tegretol, is already on the market for epilepsy. Of these, Lyrica, a follow-up product to top-selling Neurontin, may hold the most potential. Not only has Lyrica demonstrated superior clinical efficacy over Neurontin, but Pfizer has sought a broader neuropathic pain indication for the second-generation drug.

On September 2, FDA issued three approvable letters for Lyrica to treat neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia, and as adjunctive therapy in the treatment of partial seizures. (The drug did not receive approval for treating generalized anxiety disorder.) In addition, Lyrica was recently approved in the European Union for peripheral neuropathic pain and as an adjunctive therapy in the treatment of partial seizures.

Although Lyrica's approval in the European Union and approvable status in the United States is good news for Pfizer, another drug from rival Eli Lilly recently received a lot of press when it became the first medicine to be approved by FDA specifically for neuropathic pain associated with diabetic peripheral neuropathy. Cymbalta (duloxetine), a serotonin and norepinephrine reuptake inhibitor, had been given a six-month priority review and had also been approved one month earlier for major depression in adults. In the past, antidepressants were often prescribed off-label as first- and second-line pain treatments.

Despite Cymbalta's first-to-market edge in the United States, Navigant's consultants predict that after it gets FDA approval, Lyrica will eventually lead expansion of the worldwide neuropathic pain market, a segment expected to reach $3.5 billion by 2009. Last year, Neurontin, Lyrica's predecessor, alone accounted for $2.7 billion in sales, and Lyrica will likewise achieve blockbuster status.

New Approaches

Although opioids and NSAIDs—which have been around for decades—are the standard treatments for most pain indications, there are several emerging therapeutics with new mechanisms of action. This is particularly true in the neuropathic pain segment, an area in which opioids and NSAIDs have shown limited efficacy.

Elan's Prialt (ziconotide) is a synthetic form of a Conus snail venom peptide (conotoxin M-VII-A) and acts as an N-type neuron-specific calcium channel blocker. Under clinical development for chronic pain relief—including cancer, neuropathic, and postoperative pain—it is expected to provide an important new treatment option for neuropathic pain sufferers.

GW Pharmaceuticals' Sativex, a cannabinoid receptor agonist (similar to the compound in marijuana), is being developed for the UK (cancer pain, neuropathic pain, postoperative pain) and Canadian (pain, neuropathic pain) markets. Consisting of a whole plant medicinal cannabis extract, Sativex is administered as a mouth spray.

GlaxoSmithKline's Lamictal is an anticonvulsant with a novel chemical structure measured against other available drugs in its class and is thought to act as a glutamate antagonist. It is currently approved for the treatment of bipolar disorders, partial seizures, and Lennox-Gastaut syndrome in various countries and is in Phase III for neuropathic pain in the United States.

Other novel drugs expected to enter the pain market during the next five years include Novartis' Aredia (pamidronate), DOV Pharmaceutical's bicifadine, and Allergan's Botox (botulinum toxin A). Aredia, a bisphosphonate, is currently used off-label for cancer pain when cancer has metastasized to bone. Aredia is a potent inhibitor of bone resorption, thereby maintaining bone mineral density. It is thought to prevent the attachment of osteoclast precursor cells to bone. It is currently marketed for osteoporosis and other bone disorders, and is in Phase III in the US for the management of malignant bone pain. It is also under development for similar indications in Japan (Phase II) and Switzerland (unidentified clinical phase).

Bicifadine is a novel analgesic with an unidentified mechanism of action. It is understood, however, to enhance and prolong the activity of norepinephrine and serotonin and is a functional antagonist at a subset of excitatory glutamate receptors. It is under development for a broad pain indication and has been under clinical investigation for several different pain conditions, including moderate to severe postsurgical dental pain and chronic lower-back pain.

Botox, a botulinum toxin injection that paralyzes the underlying muscle, is undergoing Phase III trials for back pain (Europe and United States) as well as Phase II trials for migraine (United States) and tension headache (Canada, Europe, and United States). Although there are some novel drugs in development, most pipeline pain therapeutics are opioids and NSAIDs, which often are reformulations of products with advanced delivery systems. Therefore, new classes of drugs in the pain-management segment are limited. (See "Soon to Launch,".)

Soon to Launch : Heres a sampling of new drugs (or indications) that should be approved in the next four years.

Ronald Burch, MD, PhD, the CEO and founder of AlgoRx, explains why there are so few advances in pain management. "Pain was the first accomplishment of pharmacology, with aspirin and opiates," he says. "Therefore, little research [in this area] has been done over the last 30 years. There is more emphasis on delivery than on novel mechanisms of action."

AlgoRx is an emerging pharma company that is focused on developing products to treat pain. It has two lead products in development. The first, ALGRX 4975, is an injectable capsaicin. The compound, which is what makes chili peppers taste hot, is already used in some topical analgesics. Its second project, ALGRX 3268, is a dermal lidocaine that uses powderject technology.

Adolor is another company with a novel pain approach. Its pipeline projects target kappa opioid receptors located outside the brain rather than the mu receptors targeted by most opioid drugs, thus minimizing side effects. Adolor's Entereg (alvimopan) is under FDA review for the treatment of postoperative ileus, a painful bowel condition caused by excessive use of opioids.

Special Delivery

Advances in pain management are not limited to new drug classes or indications, but can be seen in the many ways that treatments are administered.

On the market. One widely prescribed alternative delivery system in the pain market is Johnson & Johnson's Duragesic (fentanyl patch). A single patch provides pain relief for up to three days for patients with moderate to severe chronic pain, such as cancer pain. The patch's ease of administration makes it a preferred choice among physicians, caregivers, and patients because it increases patient compliance and convenience.

Another product allowing for easy administration is Cephalon's Actiq (oral transmucosal fentanyl citrate), nicknamed the "fentanyl lollipop." Approved in 1998, Actiq is the only drug indicated for the management of breakthrough cancer pain in patients already on an around-the-clock opioid regimen. It is particularly beneficial to patients with reduced swallowing control because of its titratable dosing feature. Generating more than $237 million in 2003 revenues, prescriptions for Actiq will gradually increase as more physicians and patients become comfortable using the product.

According to physicians who participated in Navigant Consulting's Cancer Pain Physician Survey, Duragesic is especially important for cancer patients because they often have trouble ingesting medication. Consequently, it is the most commonly prescribed long-acting opioid among surveyed oncologists and pain specialists.

The survey also found that physicians who are most likely to prescribe Actiq are specialists in oncology/hematology practicing at cancer centers and universities, and those less likely to prescribe Actiq are general oncologists. This may be attributable to oncologists' higher level of comfort with traditional injectable short-acting narcotics.

In the pipeline. Many more novel drug delivery systems are now in the near-term pipeline. (See "New Delivery Pipeline," .) Some candidates combine common generic compounds with novel technologies. Others, such GW Pharmaceuticals' Sativex are both a new drug and a new delivery system (oral mucosal spray).

New Delivery Pipeline : This sample of technologies in development use effective, off-patent compounds and deliver them to patients in novel, often fast-acting ways.

Duragesic's growing popularity since its launch in 1991 has encouraged the entry of even more advanced patch technologies. To provide patients with an alternative to intravenous (IV) opioid relief as they recover from surgery, Alza (a subsidiary of J&J) is coupling its E-TRANS electrotransport technology with fentanyl, a standard opioid, to treat acute postoperative pain. While Duragesic is based on Alza's D-TRANS system, which incorporates layers of thin, flexible films, the new E-TRANS fentanyl's platform is more technologically sophisticated. Battery and button operated, the iontophoretic system applies a low-level electrical current for rapid, consistent, patient-controlled transdermal delivery. In July, FDA issued Alza an approvable letter for the product.

With its recent acquisition of Cima Labs (2004), Cephalon added OraVescent fentanyl, a sublingual (under the tongue) tablet, to its pipeline. As a follow-up product to Actiq, OraVescent boasts potentially faster drug absorption rates than its predecessor. The drug is currently in Phase III, and Cephalon expects it to launch in 2006.

Fine-tuning drug delivery methods seems to be even trickier for chronic pain indications than it is for shorter-term relief agents. To prevent the overdosage and underdosage frequently associated with pills and patches, Durect has been developing Chronogesic (sufentanil), a subcutaneous implant system that aims to provide three months of pain relief by releasing sufentanil (an opioid) in controlled doses. Although currently in Phase III, Chronogesic trials were halted in July because of problems with premature shutdown of drug delivery, and it will require product design re-engineering before development resumes.

Emerging Phase III drug candidates adopt a variety of delivery platforms, but current Phase I and II drugs involve various combinations, including inhaled, intranasal, subcutaneous, and transmucosal formulations of morphine, fentanyl, and ketamine, a nonbarbiturate anesthetic.

Abuse resistant technology. Following the October 2003 public announcement of Rush Limbaugh's addiction to Purdue Pharma's potent opioid OxyContin (extended-release oxycodone), the issue of misuse and abuse of pain medicine resurfaced. Consequently, companies developing abuse-resistant technologies are expected to contribute to the growth of the pain-management segment.

Pain Therapeutics, for example, is developing Remoxy, a long-acting oxycodone with abuse-deterrent properties. The company, which is benefiting from an accelerated development timeline granted by FDA, completed Phase I trials in mid-2004 and expects to initiate Phase III trials by the end of this year.

Remoxy is expected to be a direct competitor of OxyContin. Its success will depend on its pricing structure and negotiated reimbursement levels—how much more expensive it will be than OxyContin, especially because generic ER oxycodone will enter the market in 2005. In addition, Remoxy may be of little utility in certain patient populations, such as terminal cancer patients undergoing end-of-life care, when addiction or abuse are not issues.

As the pain-management market grows, delivery technologies that facilitate ease of use, immediate relief, and long-lasting treatment will add significant value to both current and emerging pain treatments as well as command higher pricing premiums.

More Education Needed

Despite increasing therapeutic choices for pain management, many patients remain undertreated. According to the American Pain Society (APS), only 40 percent of patients with chronic pain are appropriately treated. This statistic is explained, in part, by the lack of physician education in proper pain management. "Most physicians are trained to treat the underlying disease and not the pain that is associated with the disease," according to AlgoRx's Burch.

For example, in a survey in May of 100 physicians, most reported that their pain management education was less than satisfactory. More than 70 percent of the physicians felt that their pain management education during medical school and residency was poor. and they said they only became familiar with pain-management measures after they began practicing. Surveyed pain specialists reported that they believe even the most seasoned oncologists undertreat pain in cancer patients.

In addition, the cancer pain survey revealed that 30 percent of physicians do not follow existing treatment guidelines simply because of a lack of exposure to the latest recommended protocols. Rather, many doctors choose to prescribe products that are available at their medical facility and often revert to treating patients subjectively. Such procedural inconsistencies are unfortunate for patients because—as highlighted in a November 2003 Duke University Medical Center study—pain management in accordance with proper treatment guidelines increases the rate of pain medicine's effectiveness compared with unguided treatment.

Such systematic undertreatment negatively affects the quality of life for pain sufferers and hinders growth of the pain- management therapeutics market. "Education in pain management is the most important factor to consider in marketing efforts for a new drug," says Burch. "We must show physicians how to use the drugs that are available to them."

Pharma companies may not have the financial resources and sales force capacity to directly address unmet educational needs, but they can work with recognized organizations such as the American Pain Society for better outreach. By partnering with medical associations and patient advocacy groups to encourage physicians to participate in continued medical education on pain management, adhere to standardized guidelines, and leverage all available innovative treatment options to ensure optimal treatment of pain, in the end, pharma companies stand to benefit from greater revenues.

Pain Misconceptions

Improper treatment results not only from doctors' lack of education, but also from patients who often contribute to their own undertreatment of pain. Unfortunately, patients often hold several misconceptions about pain and relevant treatments

For example, many patients refuse opioid therapy because they are concerned about the potential for addiction. In a survey conducted by the American Pain Society, more than 80 percent of patients list addiction as a main reason for precaution involving narcotics use. Most commonly, patients confuse "tolerance" with "addiction." The need for an increased dose is a physiological sign of tolerance—not addiction. Yet the fear of becoming "hooked" is a strong deterrent against prescription pain management among many patients, especially the elderly—and some immigrants from countries such as China, whose cultures typically eschew the notion of pain treatment—who have not been reached by pain-management education efforts.

In addition, patients with serious medical conditions generally expect to endure a certain level of pain. Cancer patients often assume pain to be an inevitable adverse effect of their disease and related treatments such as chemotherapy. As a result, many do not actively seek pharmacological relief from chronic symptoms.

Some doctors suffer similar misconceptions. In fact, some oncologists identify pain as a physical marker in the diagnosis and prognosis of cancer. Changing degrees of pain, some physicians claim, inform them about the status of their patients' cancer development. This misconception disregards patient comfort level and leads to preventable suffering and reduced quality of life.

Competitive Arena

The pain-management market has many well-established brand and generic players, and strong competition is a substantial barrier to entry for new companies. But those interested in entering it must target niche markets (such as abuse-resistant products) or form strategic partnerships with current players.

Brand companies also face strong generic competition. In 2005, blockbuster drugs Duragesic and OxyContin will go off-patent and face the possibility of losing significant market share. Currently, J&J's Duragesic is the only marketed pain therapeutic to use the transdermal patch technology, although others are in the pipeline, including a generic from Endo and Alza's E-TRANS fentanyl.

OxyContin will also lose significant market share. Endo, the first generic manufacturer of extended-release oxycodone, will enjoy 180 days of market exclusivity. Market erosion will increase after the exclusivity period ends and other generic players enter the market. But the competition will not be as widespread as it is for other drugs because many generics companies simply do not enter the narcotics market.

To combat generic competition, brand manufacturers must find ways to obtain patent extensions on their products through improved formulations and expanded indications. But such strategies may not be effective if there is a lack of demand for their products or resistance to their prices. For example, some pharmacies and hospitals do not carry newer or more expensive products with sophisticated delivery systems, such as Actiq.

Companies with new, follow-on products seeking to win back market share lost to generics must find ways to speed the adoption of their drugs, whether by providing compelling data from head-to-head studies or sustaining robust marketing and salesforce efforts.

The market for pain-management therapeutics is still maturing, with the release of next-generation products, alternative drug-delivery systems, and even some new drug classes. Pain-management therapeutics may not be first-line treatments for cancer, diabetes, and other serious diseases, but they should be—when appropriate—regular adjuvant therapies used to help patients improve their quality of life and enhance physical and psychological endurance in coping with illness. But the industry must recognize that expansion of the market, which in turn drives research and development, is contingent on continuing physician education and positive patient response.