Many conditions require medication to relieve chronic, intractable pain. Cancer patients, surgical patients, and those suffering from low-back pain or other musculoskeletal conditions often seek relief from their pain through pharmaceutical intervention.
Taking into account time lost from work and visits to a health care provider, the cost of treating pain totals around $100 billion annually. Americans spend about $3 billion each year on over-the-counter pain treatment and another $750 million for prescription drugs. At some point, 45 percent of the population seeks medical intervention to treat pain, according to the American Pain Society.
To that end, pharmaceutical manufacturers continue to seek more effective and safer ways to relieve Americans of some of the burden of chronic pain.
One of the most recent entrants to the pain market is Chirocaine (levobupivacaine injection), available in single doses of 10 mL and 30 mL. Approved in 1999 for use mainly in minor surgery and during childbirth, the FDA extended the drug’s indication to include local or regional anesthesia during surgery and postoperative pain early in 2000.
Levobupivacaine is a pure levo-isomer of the widely used anesthetic bupivacaine, which is not indicated for post-operative pain. While levobupivacaine has shown equivalent potency to bupivacaine, it demonstrates a much better safety profile in relation to cardiac and central nervous system toxicity, and the FDA has ruled that Chirocaine will not be required to carry a black-box warning about potential cardiac events. Developed by Chiroscience, Chirocaine is being marketed in the U.S. by Purdue Pharma L.P.
Precedex (dexmedetomidine HCl injection) was approved for Abbott Laboratories late in 1999. Indicated for sedation of patients in an intensive care setting, a loading dose of 1 mcg/kg over 10 minutes is followed by an infusion of 0.2 to 0.7 mcg/kg per hour, that should not exceed 24 hours. However, patients with renal or hepatic impairment may require lower doses. With its sedating effects, Precedex appears to lower the amount of pain medication needed. Approval is still pending in Canada and Europe.
In early 1999, Endo Pharmaceuticals launched Zydone (hydrocodone bitartrate and acetaminophen) tablets for the management of pain. Each Zydone tablet contains 400 mg of acetaminophen, with three different doses of hydrocodone available – 5 mg, 7.5 mg, and 10 mg. Zydone is generally well tolerated, and with the most frequent adverse events being lightheadedness, dizziness, and sedation.
In December 1999, Endo’s Percocet CII (oxycodone HCl and acetaminophen tablets, USP) became available in three new strengths. The original formulation contains 5 mg oxycodone HCl and 325 mg acetaminophen and is now called Percocet-5/325. The new strengths are known as Percocet-2.5/325, Percocet-7.5/500, and Percocet-10/650.
The FDA approved Actiq (transmucosal fentanyl citrate) in late 1998 for cancer patients who experience severe breakthrough pain after using other narcotics. Actiq uses Anesta Corporation’s unique transmucosal delivery system and is packaged as a raspberry-flavored lozenge on a stick. Patients on coagulative therapies should not use Actiq.
In March of last year, a new, higher dose of Duraclon (clonidine HCl injection) became available. Duraclon, which was previously available as a 100 mcg/mL solution, now offers a 500 mcg/mL dose. Roxane Laboratories’ centrally acting analgesic is indicated as a combination when opioid analgesics alone can’t stop severe pain in cancer patients.
Purdue Pharma L.P.’s, OxyContin (oxycodone HCl controlled-release) Tablets C-II became available in a 160 mg strength in July of 2000. Indicated for moderate to severe pain, OxyContin – a 12-hour oxycodone analgesic – was initially available in 10 mg, 20 mg, and 40 mg tablets, with an 80 mg dosage that came to market in 1997. This newest strength, to be used only in opioid-tolerant patients requiring daily doses of 320 mg or more, allows patients requiring these higher doses to take considerably fewer tablets.
In 1998, Algos Pharmaceuticals filed an NDA for its product MorphiDex, a patented combination of morphine and the NMDA-receptor antagonist dextromethorphan. With an intended indication for relief of cancer pain, MorphiDex showed rapid pain relief for up to eight hours and superior results over morphine alone in clinical trials. However in August of 1999, the FDA – over questions regarding clinical trials, toxicology models, and a high-dose pharmacokinetic trial – issued a non-approvable for MorphiDex. Algos is currently working with the FDA to resolve these concerns and hopes to continue to move the drug toward market.
Chiesi Farmaceutici’s Brexidol (piroxicam-beta-cyclodextrin), which was approved in Canada in 1999 for the treatment of acute pain, is currently awaiting approval in both the U.S. and Europe.
Naropin (ropivacaine HCl) was recently approved for extending the duration of treatment for post operative analgesia using the 2 mg/mL dosage. In 1996, Astra USA’s drug received approval for obstetric and regional anesthesia for surgery and is currently available in four different strengths.
G.D. Searle is awaiting approval of a new indication for its COX-2 inhibitor, Celebrex, which is currently approved for both adult rheumatoid arthritis and osteoarthritis. Clinical trials treating post-surgical pain show that celecoxib’s efficacy is similar to the commonly used combination of hydrocodone and acetaminophen. In addition, the results of an analysis between January and June of 1999 including data equivalent to 280 million people showed that it is significantly safer than traditional treatments for pain and inflammatory conditions.
In the very early stages of pre-clinical development, a compound known as osteoprotegerin (OPG) stopped the growth of osteoclasts, the cells believed to cause the bone destruction associated with cancer. Researchers have found that blocking osteoclasts decreases the extent of pain that accompanies cancer affecting the skeletal structure, such as cancers of the breast or prostate. In addition, OPG appears to block the spinal cord changes that occur with these cancers. Although these effects have yet to be replicated in humans, researchers are hopeful that these positive findings will help them unlock the key to the basic mechanism of bone pain related to cancer. If studies in humans prove successful, bone pain eventually may be treated with OPG and radiation.
Other therapies waiting in the wings include two formulations of ketoprofen being developed at Noven – one, a transmucosal agent for dental pain in pre-clinical development; the other a transdermal is currently in Phase II trials seeking an indication for pain relief. GW275919 is being studied at Glaxo for pain and inflammation with an estimated NDA filing date sometime in 2003.
In addition to the treatment of arthritis, both Pharmacia and Searle are also studying valdecoxib for pain management.
In addition, Searle is developing an injectable COX-2 inhibitor, parecoxib, to treat acute pain primarily in a hospital setting.