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News & a N alysis

FROM THE ANAlyST’S COUCH

Pain market

Irena Melnikova

FROM THE ANAlyST’S COUCH Pain market Irena Melnikova ‘Chaise Vari’ designed by Héctor Esrawe Pain is

‘Chaise Vari’

designed by

Héctor Esrawe

Pain is the most common symptom for which patients seek medical attention. According to the American Pain Society, prevalence of chronic pain in the United States is estimated to be 35.5% or 105 million people 1 . This costs more than US$100 billion per year in direct health-care expenditure and lost work time. Some of the conditions most frequently associated with acute and chronic pain are illustrated in FIG. 1. Current pain management relies heavily on agents that have long been known to have analgesic properties. Non-narcotic analgesics (acetominophen and aspirin), narcotic analgesics (opioids), non-steroidal anti-inflammatory drugs (NSAIDs), and thermal agents continue to be the mainstays of pain management. More recently, other medicines have been added, such as antidepressants, anticonvulsants and selective cyclooxygenase 2 (COX2) inhibitors. Since 2004, concern over the cardiovascular safety of the COX2 drug class has led to a continuous decline in its market share in favour of NSAIDs and opioids. Although current analgesic drugs help many, only an estimated one in four of those with pain achieves adequate relief. Currently approved drugs are also often associated with poor tolerability, unfavourable side effects, concerns over long-term safety and abuse potential, as well as inconvenience of use 2 . Clearly, new efficacious and safe analgesic agents are needed. Strategies to address the unmet need can be broken down into three basic approaches: reformulation and novel delivery approaches of existing agents; targeting new indications and specific patient populations; and development of drugs with a novel mechanism of action.

Novel formulations Many companies are working on reformulations of existing analgesic agents that have proven efficacy and safety. This strategy significantly reduces the development risks and cost factors. In fact, most new pain therapeutics approved in recent years are new formulations of existing drugs. Opioids are still considered to be the most effective therapeutic option for serious pain. This drug class holds the major share of the

pain market (FIG. 2). But in addition to serious side effects, such as respiratory depression, major concerns around opioid use include the risk of addiction, abuse, misuse, and diversion. In February 2009, the US FDA announced that it would require manufacturers of high potency opioids to implement risk evaluation and mitigation strategies to address these risks 2 . This policy is anticipated to benefit long-acting agents and ‘abuse deterrent’ formulations, which are designed to prevent misuse and negate euphoric effects of opioids. Examples include the recently approved oxycodone controlled-release formulation (OxyContin; Purdue Pharma) and the morphine/naltrexone combination (Embeda; King Pharma), as well as several candidates awaiting regulatory approval such as long-acting oxycodone (Remoxy; King Pharma/Pain Therapeutics) and oxycodone/ niacin (Acurox; King Pharma/Acura Pharmaceuticals) (FIG. 3). However, it should be noted that Acurox received a negative vote (19–1) from an FDA advisory panel in April 2010, making its approval doubtful. The risks of serious or fatal gastrointestinal (GI) bleeding from NSAIDs are well established 2 . Several drug candidates are being developed that combine a GI protectant with an NSAID in a single tablet. A combination of proton pump inhibitor esomeprazole with naproxen (Vimovo; Pozen/AstraZeneca) and the combination of histamine receptor H 2 antagonist famotidine with ibuprofen (Duexa; Horizon Pharma) are currently under review by the FDA. In clinical trials, both combination formulations significantly reduced the incidence of NSAID-induced GI ulcers in patients with mild-to-moderate pain due to arthritis.

New indications Eli Lilly’s antidepressant duloxetine (Cymbalta) and Pfizer’s anticonvulsant pregabalin (Lyrica) have been approved for various types of neuropathic pain 3 and fibromyalgia 4 (FIG. 3). Milnacipran, which was originally approved in the 1980s in Europe for depression, was developed for fibromyalgia by Forest/Cypress (under the trade name Savella) and was launched in the United States in 2009 (FIG. 3). These agents have contributed to the resumption of growth

in the pain market over the past few years,

and addition of new indications are expected

to expand it further.

Drugs with a novel mechanism of action For centuries, pain has been viewed as a symptom accompanying another disease. Therefore, therapy has been geared towards symptom reduction as opposed to treating the underlying cause. Only more recently, it was

recognized that pain, in particular chronic pain, is a disease itself. Advances in understanding the molecular mechanisms of pain produced multiple potential drug targets for analgesia. Nerve growth factor (NGF) plays a crucial role in the generation of pain and hyperalgesia in several acute and chronic pain states. Antagonizing NGF is one of the new approaches in drug development for pain. Several NGF-specific antibodies are in Phase II/

III trials, including tanezumab (Pfizer),

SAR164877/REGN475 (Sanofi–Aventis/ Regeneron) and JNJ-42160443/AMG403 (Johnson & Johnson/Amgen). If approved

(anticipated in 2012), Pfizer’s tanezumab will

be the first biologic for treating chronic

pain, and could become the first drug to be specifically approved for lower back pain. Glial cells are promising new targets

for the treatment of chronic neuropathic

pain. Glial cell modulators, when used in combination with opioids, may also increase the efficacy of opioids and therefore reduce drug dependence and tolerance. A couple of glial cell modulators are in early clinical development: Solace Pharmaceuticals’s SLC022 is currently in Phase IIa and Biogen Idec’s neublastin is in Phase I clinical trials. Owing to increased regulatory concern over the risk–benefit profiles of drugs, analgesic agents with novel mechanisms of action are anticipated to receive rather narrow labels. But, because of the unmet need in pain management, even a small market share could translate into a significant business opportunity. As pain is a complex phenomenon

that results from a sum of contributing factors,

no single drug with a novel mechanism of

action is expected to be a silver bullet for pain management. A rational combination therapy approach that targets key peripheral and central pain mechanisms and modulating pathways may yield the best outcomes.

NATURE REVIEwS | Drug Discovery

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pAiN | market iNDicators

The global pain market in 2009 was valued at over US$50 billion, including $27 billion in the seven major economies (the US, Japan, France, Germany, Italy, Spain and the UK) (FIG. 2). An ageing population, increases in the prevalence of chronic painful conditions, new product approvals, as well as improvements in education of both physician and patients regarding available treatment options should continue to sustain the growth and further development of this market. Owing to the availability of generic compounds, pricing will become an important consideration and only a limited number of new products are projected to achieve blockbuster status (sales over $1 billion) (FIG. 3). Thus, novel agents are unlikely to displace any of the currently approved drug classes and are likely to be indicated for use in specific patient populations.

Irena Melnikova, Ph.D., is a Principal at TVM Capital, 101 Arch Street, Boston, Massachusetts 02110, USA. e‑mail: melnikova@tvm‑capital.com

doi:10.1038/nrd3226

Published online 23 July 2010

1. Harstall, C. How prevalent is chronic pain? Pain Clinical Updates X, 1–4 (2003).

2. Woodcock, J. A difficult balance — pain management, drug safety, and the FDA. N. Engl. J. Med. 361, 2105–2107 (2009).

3. Dworkin, R. H. et al. Recommendations for the pharmacological management of neuropathic pain. Mayo Clin. Proc. 85 (Suppl. 3), 3–14 (2010).

4. Arnold, L. M. Strategies for managing fibromyalgia. Am. J. Med. 122 (Suppl. 12), 31–43 (2009).

Competing interests statement

The author declares no competing financial interests.

FUrtHer iNFormatioN Us National library of Medicine and National institutes of Health — Pain:
FUrtHer iNFormatioN
Us National library of Medicine and National institutes of
Health — Pain: http://www.nlm.nih.gov/medlineplus/pain.html
The Pain Clinic: http://www.painclinic.org
All links Are AcTive in The online PDF
Local
anaesthetics COX2 Strong (5%) inhibitors opioids (7%) (29%) Weak opioids (7%) Anti- depressants US$27 billion
anaesthetics
COX2
Strong
(5%)
inhibitors
opioids
(7%)
(29%)
Weak
opioids
(7%)
Anti-
depressants
US$27 billion
(11%)
Anti-
convulsants
NSAIDs
(13%)
(28%)

Figure 2 | Total value and market share by sales in the seven major pharmaceutical markets of major pain drug classes in 2009. Market shares of major drug classes as sales percentages of the total are indicated. NSAIDs, non-steroidal anti-inflammatory drugs. Sources:

Datamonitor, IMS Health, Decision Resources.

Pain

Acute Chronic Nociceptive Neuropathic Central Peripheral • Post-stroke • Injury • Multiple sclerosis •
Acute
Chronic
Nociceptive
Neuropathic
Central
Peripheral
• Post-stroke
• Injury
• Multiple sclerosis
• Post-operative
• Spinal cord injury
flare
• Migraine (31 million)
• HIV related neuropathic
pain (0.3 million)

Osteoarthritis (16 million) Rheumatoid arthritis (2.5 million)

(3.2 million)

Visceral Mixed
Visceral
Mixed

Internal organ

Pancreatitis

Inflammatory

bowel syndrome

Post-herpetic neuralgia (0.11 million)

Diabetic neuropathy

neuralgia (0.11 million) • Diabetic neuropathy • • Lower back (55 million) Cancer (1.5 million)

Lower back

(55 million)

Cancer

(1.5 million)

(6 million)

Fibromyalgia

Figure 1 | Pain classification and representative indications. Distinguishing between different types of pain is critical for proper treatment. Pain can be classified by its duration into acute and chronic pain. Chronic pain is further classified by the source of pain production: nociceptive pain, which is transmitted by nociceptors from the site of injury or tissue damage (for example, inflamed joints in arthritis); neuropathic pain, which is initiated or caused by a primary lesion or dysfunction in the nervous system (further subdivided into central and peripheral, involving the central and peripheral nervous systems, respectively); visceral pain, which involves the internal organs; mixed pain, which is of mixed origin. Prevalence for selected chronic pain conditions in the United States is indicated. Sources: Centers for Disease Control and Prevention, National Center for Health Statistics, Arthritis Foundation, National Institutes of Diabetes and Digestive and Kidney Diseases, American Pain Society, The American Pain Foundation.

4.5 4.05 4.0 3.5 3.75 2.9 3.0 2.5 2.0 1.5 1.0 0.86 1.0 0.55 0.45
4.5
4.05
4.0
3.5
3.75
2.9
3.0
2.5
2.0
1.5
1.0
0.86
1.0
0.55
0.45
0.40
0.5
0.30
0
OxyContin
Remoxy
Embeda
Lidoderm
Duragesic
OFIRMEV
Lyrica
Cymbalta
Savella
US$ billion

Figure 3 | Projected annual peak sales of selected pain drugs representative for the various categories of pain medications. OxyContin (controlled-release oxycodone; Purdue Pharma), Remoxy (long-acting oxycodone; King Pharma/Pain Therapeutics) and Embeda (morphine plus naltrexone; King Pharma) are oral formulations. Lidoderm (5% lidocaince patch; Endo) and Duragesic (transdermal fentanyl; Johnson & Johnson) are topical formulations. OFIRMEV (intravenous acetaminophen; Cadence) is an injectable. Lyrica (pregabalin; Pfizer) is an anticonvulsant. Cymbalta (duloxetine; Eli Lilly) and Savella (milnacipran; Forest/Cypress) are antidepressants. All drugs are on the market except for Remoxy and OFIRMEV; the new drug application for Remoxy is anticipated to be re-submitted in the fourth quarter this year, and OFIRMEV is anticipated to be approved in the third quarter of this year. Numbers for Lyrica and Cymbalta indicate sales in all indications. Approximately 30–35% of Lyrica prescriptions are estimated to be for neuropathic pain and fibromyalgia. Approximately 20–25% of Cymbalta prescriptions are for neuropathic pain and fibromyalgia. Sources: company information, analyst reports.

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