Safety Issues Dominate Pain Market

Pain relief has in some ways become, both linguistically and as an endeavor, a metaphor for the larger pharmaceutical industry. Today’s pain market is vibrant and growing, but more focused on risk avoidance or mitigation than on innovation As a consequence, resources that might have been devoted to developing new classes of pain drugs become diverted to making centuries-old painkillers safer and less attractive to abusers.

IMS Health calculated the 2008 US market for prescription pain products at $8.2 billion, up 7.6% over the year before, but up only 8.4% since 2004 (Fig. 1, p. 18). Kalorama Information (New York) estimated the global market for prescription pain products at $26.1 billion in 2006, with drugs comprising 90% of the market’s revenues. According to their report, “The World Market For Pain Management Drugs And Devices,” sales will grow approximately 6% per year through 2010, to $33.2 billion.

The paucity of new pain drugs has not been for lack of effort. Pfizer’s experience with its Celebrex COX-2 inhibitor illustrates the types of issues facing developers. Approved in 1998, Celebrex became the number-one painkiller in 2004 on sales of $3.3 billion. The following year prescriptions plummeted in the aftermath of the Vioxx debacle, which cast a shadow over all COX-2 agents. Celebrex now carries a “black box” warning to reflect higher cardiovascular risk, but sales have risen, to $2.3 billion in 2008 (per IMS Health data), on the heels of recent non-approvable decisions for competing drugs.

What’s in a name?

Pain drugs are conveniently classified into three categories, roughly by mode of action: opioids, the oldest grouping and the one with the highest abuse potential; non-steroidal anti-inflammatory drugs (NSAIDs), which include non-prescription painkillers like ibuprofen as well as prescription-only COX-2 inhibitors; “others,” which work not on nerves or inflammation but on underlying pain mechanisms.

Another view differentiates drugs that relieve “nociceptive” pain caused by tissue damage or injury from those that act on “neuropathic” pain from diabetes, cancer, and other diseases. The opioids and NSAIDs fall into the first category, while antidepressants, anticonvulsives and topical treatments are used on the latter. “Most pipeline drugs for noiceptive pain consist of reformulations. Neuropathic pain research is where most of the interesting science is going on,” says Terence McManus, PhD, lead analyst for neurology at Datamonitor (London, UK).

As a class, opioids are a close second, to cholesterol agents, in total prescriptions but only fifteenth in sales revenue, thus the perfect storm of low cost, high availability, and abuse potential.

Five million Americans reported using opioid drugs recreationally in 2006. Total annual costs of opioid abuse were as high as $400 billion when care, accidents, legal proceedings, law enforcement, incarceration, and lost productivity are taken into account.

According to the Centers for Disease Control and Prevention, deaths from opioid painkillers have more than tripled since 1999, from 4,000 per year to nearly 14,000 in 2006. Popular agents of abuse include methadone, morphine, oxycodone, hydromorphone, and hydrocodone (the most-prescribed drug in the U.S. with 117 million scripts per year). Half of all overdose deaths involve mixing painkillers with other nervous system agents like tranquilizers.

The rationale for introducing the non-narcotic COX-2 inhibitors and their predecessors, the NSAIDs, was the promise of aspirin’s benefits without its main side effect, stomach bleeding. NSAIDs and acetaminophen are now largely OTC medicines, although prescription-strength formulations exist as well; the COX-2 inhibitors remain prescription-only.

OTC status, and the inability of NSAIDs and COX-2 to induce euphoria, lulled consumers into a false sense of safety with these drugs, however. In the mid-2000s COX-2 agents’ troubles arose from their cardiovascular risk but their stomach safety is also an issue. Perhaps more startling is the fact that OTC pain remedies cause 130,000 hospitalizations and 19,000 deaths in the US per year as a result of damage to the liver, kidneys, and heart. As of April, 2009, OTC analgesics carry bold warnings for severe liver damage (Tylenol/acetaminophen) and stomach bleeding (NSAIDs).

Quest for innovation

Although pain-drug companies seem preoccupied with reformulating old medicines, particularly the opioids and NSAIDs, innovation is occurring. For example Nucynta (tapentadol; Johnson & Johnson), a centrally-acting pain drug that works through a novel mechanism, was approved in late 2008 but due to its abuse potential was classified as a Schedule II controlled substance in early 2009. Notable Phase III-stage pain drugs include Winston Pharmaceuticals’ Civamide, a topical formulation of the active ingredient in hot pepper, Pfizer’s tanezumab, a protein drug that reduces arthritis pain, and Naproxcinod from NicOX (Sophia Antipolis, France). Naproxcinod belongs to a novel NSAID category, the CINODs (COX-inhibiting nitric oxide donators), which work like COX-2 agents but are gentler on the stomach and do not raise blood pressure.

Among drugs in the “other” category are the triptans, for treating migraine. Triptans work through novel pain-killing mechanisms and have zero abuse potential, but they do not work for plain vanilla headache or muscle soreness. Merck recently sought a migraine-prevention indication for telcagepant, a new triptan agent, but liver toxicity made the drug unsuitable for long-term preventive use. The company has re-positioned telcagepant as a treatment for acute migraine and plans to apply for marketing approval in 2010.

Hot on the heels of the Phase III compounds are the ion channel agents, which control the flow of electrically charged chemicals into and out of cells. Icagen (Durham, NC) and Pfizer (New York) are collaborating on sodium-channel pain drugs; Newron (Milan, Italy) has a development-stage calcium channel agent, as do partners Xenoport (Santa Clara, CA) and GlaxoSmithKline (Middlesex, UK). Lead ion-channel agents are currently in Phases I/II.

Next in line are early-stage agents including the opioid receptor ligands, bradykinin antagonists, mPGES-1 inhibitors, glutamate receptor antagonists, substance P and neurokinin receptor antagonists, P2X2 neuron receptor antagonists, cannabinoids, fish and cone shell toxins, cell and gene therapies.

Like their colleagues in non-pain areas, developers of analgesics are considering “personalizing” pain drugs by bundling them with tests that identify patients likely to benefit or suffer harm. After FDA rejected Novartis’s (Zurich, Switzerland) Prexige COX-2 agent due to liver toxicity, the company considered resubmitting the drug with a genetic test for predisposition to liver problems. Novartis confirmed last summer that a test was forthcoming, but the drug-diagnostic combination would not be re-submitted for US approval. The personalization route is unlikely to work with opioids because individuals in whom those drugs do not induce euphoria, or who are less prone to addiction, are unlikely to experience pain relief.

Opioids: A special case?

Rightly or wrongly, stakeholders are much more concerned over opioid safety than they are with NSAIDs. The infatuation with addiction, it seems, is itself addictive. Robert Rapoport, MD, who reviews anesthesia and analgesia products at FDA, summarized the problem in an interview in Nature last year. Acknowledging the equilibrium between legitimate pain relief and abuse, noted that “we have made incremental advances but remain far from achieving that balance.”

The principal strategies that have evolved to curb opioid diversion and misuse are monitoring, post-marketing mandates, law enforcement, and formulation.

Forty states monitor painkiller use by law, but the numbers of abusers and prescribers are so large only the most egregious are apprehended, and just a small percentage of them actually convicted.

In 2005, a national bill to monitor the use of prescribed controlled substances passed both houses of Congress unanimously and was signed by President Bush. Critics have warned that as written the law, National All Schedules Prescription Electronic Reporting Act (NASPER), permits government to investigate prescription histories for any reason. For now the issue is moot, however, since Congress has only appropriated $2 million to the program thus far.

The main reporting mechanism for opioids is the nonprofit Denver-based Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) program, initiated in 2002 by Purdue Pharma (Stamford, CT), a manufacturer of opioid pain products. RADARS collects information from poison control centers, treatment programs, surveys, and physicians to create a zip code-level demographic map of abuse. Similarly, the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO), is a subscription-based risk-management program for high-risk drugs including drugs of abuse.

RADARS provides more generic information on classes of painkillers, for example extended- vs. immediate-release, where NAVIPPRO homes in on individual brands. NAVIPPRO is managed by Inflexxion (Newton, MA), a firm that consults on pharmacovigilance and health-related behavioral programs.

Dr. David Kloth, past president and board member of the American Society of Interventional Pain Physicians, believes that if properly funded NASPER could pay for itself many times over. “The savings from prescription monitoring would be astronomical in terms of higher worker productivity, lower law enforcement costs, and ruined lives.”

Kloth is not as confident in pure enforcement strategies, which he says has been largely ineffective due to the size of the opioid problem and the cost and difficulty of convicting physicians. Despite the existence of pill mills, and widespread opioid tourism involving the rental of buses and airplanes to abuse-friendly jurisdictions, “They don’t go after you unless you’re really, really bad.”

FDA announced early in 2009 that it was considering a class-wide Risk Evaluation and Mitigation Strategy (REMS) for extended-release opioids. REMS (see Pharmaceutical Commerce, Nov/Dec 2009, p. 1) are post-approval measures to ensure that a product’s benefits continue to outweigh risks. REMS may include any combination of label warnings, education or training for prescribers and dispensers, mandatory registries, individual monitoring, and restricted dispensing.

Extended release products have turned out to be the proverbial road to hell paved with good intentions. They are safe when used as directed, but abusers easily manipulate extended release formulations to release large doses of opioids.

A class-wide REMS will not occur for opioids until at least late 2010, as FDA has extended the comment period for implementation by one year (until October 2010). Until then, approvals and post-marketing commitments will be considered on a case-by-case basis. For example, FDA recently issued a REMS for the fentanyl drug Onsolis (Meda Pharmaceuticals). Fentanyl, an opioid 100 times stronger than morphine, is a favorite with abusers. The Onsolis REMS, named FOCUS (Full Ongoing Commitment to User Safety) mandates that prescribers must register the patient by fax and submit the original prescription to an approved, participating pharmacy by courier, which delivers the drug directly to the patient’s home (Pharmaceutical Commerce, July/Aug, 2009, p. 9).

Like David Kloth, practicing physician Jayson Hymes, MD, director of Conservative Care Specialists (Van Nuys, CA) and a government pain medicine consultant, believes physician education, training and certification are the keys to reducing prescription drug abuse. “More physicians call themselves ‘pain doctors,’ mainly for financial reasons, than have actually been trained as such. Pain medicine is whatever the practitioner says it is. Only when mandatory, official certification becomes the norm will we have enforceable standards.”

Most opioid postmarketing studies focus on abuse and diversion, not on patients using the drug as directed. “And I don’t see that changing any time soon,” comments Edgar Adams, MD, executive director for epidemiology at Covance (Conshohocken, PA).

Postmarketing studies on the painkiller Tramadol, in which Dr. Adams was intimately involved, are a model of how such plans can work. Tramadol was approved in the United States in 1994 under the condition that the sponsor undertake postmarketing surveillance. The program, overseen by an Independent Steering Committee of which Dr. Adams was a founder, included an 11,000-patient abuse and addiction-potential study. Through the success of this program, tramadol remains unscheduled everywhere except for two states (Kentucky and Arkansas).

Covance has developed an opioid monitoring program with two partners (eRx Network (Nashville, TN and Analgesic Research (Needham, MA). The system, which operates within pharmacies’ existing method of communicating with insurers, registers the patient, verifies their opioid-tolerance, and is expected to satisfy REMS requirements for monitoring opioid prescriptions and patients. “The process will add one-tenth of a second to the pharmacy transaction, and will greatly reduce the burden associated with other monitoring methods” says Dr. Adams. Covance has already submitted an NDA employing the new system.

Formulation strategies: still lively

Formulation strategies for thwarting abuse, which form the core of today’s analgesia “specialty pharma” market, include pharmacologic, physical, and aversion techniques. All go at least one step beyond conventional “modified release.”

On the pharmacologic front King Pharmaceuticals’ (Bristol, TN) Embeda pain pill includes extended-release morphine formulation, and a “sequestered core” of naltrexone—a second drug that counteracts morphine if abusers try to extract the opioid all at once.

Analogously, combining NSAIDs with a second agent to protect the stomach may be a viable strategy for reducing serious side effects of OTC painkillers. Horizon Therapeutics (Northbrook, IL) recently completed a large Phase III study on HZT-501, which combines prescription-strength doses of ibuprofen and famotidine. The first drug treats pain, the second reduces stomach acid. Clinical data suggest a 50% decrease in serious stomach ailments in patients taking three to four pills daily.

Since both active ingredients are generics, Horizon will apply for approval under a 505(b)2 “special protocol assessment.” The big question is what will appear on the drug’s label. Prescription famotidine was approved for treating ulcers, while its OTC brands (e.g. Pepcid) claim to reduce stomach acid. Marketing a “safer ibuprofen” would be a huge feather in Horizon’s cap but only FDA can determine if that claim is valid. Jeff Shermann, MD, Horizon’s chief medical officer, would only say that “our claims will be linked to those in package inserts for prescription doses of both ingredients.”

Physical barrier strategies include the OraDur formulation, from Durect (Cupertino, CA), which embeds the drug in a highly viscous inert material that is difficult to crush or chew, and from which extracting the active ingredient is extremely difficult. OraDur forms the basis of Remoxy, a sustained-release version of oxycodone jointly developed by Durect and Pain Therapeutics (San Mateo, CA). The sponsors had hoped for an abuse-resistance claim for Remoxy but FDA demurred. Remoxy has now been acquired by King.

Aversion strategies thwart thrill-seekers with a side effect that negates the euphoria. In partnership with Acura Pharmaceuticals (Palatine, IL), King is developing Acurox, an NDA-stage, immediate-release oxycodone-plus-niacin formulation. Niacin, a B-vitamin, causes an uncomfortable flushing sensation when taken in excess.

Obtaining expanded safety labeling requires clinical testing specifically designed to demonstrate the new claim, and data analysis supporting the application. From a regulatory standpoint this is mostly uncharted territory, since a claim of lower abuse potential involves consequences that are difficult to quantify. Consequently, it is easy for companies to get in trouble with regulators. “The area is so new that the regulatory guidelines are still undeveloped,” observes Linda Wace, MD, EVP of medical affairs at King.

Embeda was approved with a REMS due to the product’s “potential for abuse, misuse, overdose, and addiction,” according to an FDA warning letter issued to King on 21 October, 2009. FDA was concerned that King video news releases were “false or misleading” because they minimized Embeda’s risks and strayed too far from the drug’s approved indication.”

King has gone to extraordinary measures but its success in obtaining expanded safety claims is uncertain. The company routinely subjects its products to extraction and tampering tests, and conducts “abuse liability” studies where recreational drug abuser-subjects rate products blindly. “We ask them how high they get,” Wace says.

FDA—as would any pain sufferer or healthcare provider—would like better options for pain management, but until new drugs appear, FDA is trying to make the best of a difficult situation. “Despite increased awareness of the harm resulting from the use of [today’s pain drugs], it is likely that extensive prescribing and use of these drugs will continue,” wrote Janet Woodcock, MD, director of CDER at FDA, in the Nov. 26th issue of the New England Journal of Medicine. “Given this reality, there is a need for more vigorous risk management efforts by FDA and other stakeholders in the health care system.” PC