Given the aging of the population and the increasing prevalence of chronic pain, this author interviews leading researchers and clinicians about new modalities and reemerging medications that may have a significant impact for patients.

Are there alternative medications for treating osteoarthritis (OA)? What should you know about the three drugs that have recently garnered approval from the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis? Can a new osteoporosis medication facilitate improved patient compliance? For the answers to these questions and more, this author talked to leading experts to get their thoughts on both new medications and reemerging drugs for arthritis and musculoskeletal conditions.



1. Sodium hyaluronate (Hyalgan, Sanofi Aventis). Hyalgan is currently indicated for OA knee pain in patients who have had an inadequate response to conservative therapy and simple analgesics. However, a recent study presented at the American College of Rheumatology Annual Scientific Meeting in November suggested that Hyalgan may be beneficial for patients with OA pain in the shoulder.

The double-blind, randomized study involved more than 600 patients who suffered from moderate to severe shoulder pain due to OA, rotator cuff repair and/or adhesive capsulitis. The study showed that patients receiving either three to five weekly injections of Hyalgan over a six-month period had a statistically significant reduction in pain.

Roy Altman, MD, the lead researcher of the study, says the results show that “Hyalgan relieves shoulder pain in the majority of patients with osteoarthritis of the shoulder.”

Nathan Wei, MD, FACP, FACR, notes that he has also had success using viscosupplements to treat chronic shoulder pain that has not responded to intraarticular steroid injections.

“Viscosupplements appear to work best for people who have an osteoarthritis component to their shoulder problem,” explained Dr. Wei in a previous issue (see page 8, “News And Trends,” January/February issue).
Overall, in regard to Hyalgan, Drs. Altman and Wei have both had favorable experiences with the drug in treating OA. Dr. Altman, a Professor of Medicine within the Division of Rheumatology at the University of California, cites the drug’s “sustained response (in patients who respond to the therapy) and lack of adverse reactions.” However, he notes that Hyalgan has “less benefit with the more advanced osteoarthritis.”
Both doctors note that the drug’s mechanism of action is currently unknown. However, Dr. Altman says recent research suggests that Hyalgan “reduces the inflammatory action of the synovium and cartilage cells by blocking intracellular inflammatory pathways.”

Curtailing The Progression Of Osteoarthritis?
2. Doxycycline. Many medications can be helpful in managing the painful symptoms of osteoarthritis but very few can prevent the progression of the disease. However, doxycycline may have potential promise in this area, according to Deborah Brown, APRN, BC, MSN.

Brown cites the findings from a randomized, double-blind trial on doxycycline that was published in the July 2005 issue of Arthritis and Rheumatism. The study evaluated more than 400 overweight women between the ages of 45 to 64 who had documented monoarticular medial tibiofemoral component osteoarthritis.

On average, patients in the doxycycline treatment group had 40 percent less loss of joint space narrowing (JSN) than the placebo group at 16 months. At 30 months, patients in the doxycycline group averaged 33 percent less loss of JSN than the placebo group.

While the FDA has not approved doxycycline for the treatment of OA, Brown says the study reveals the drug may have an impact in curtailing the development of the disease.

“This study reveals very exciting news regarding the potential for slowing the progression of osteoarthritis,” says Brown, an Orthopaedic Nurse Practitioner at the Beth Israel Deaconess Medical Center in Boston.
According to Brown, the study shows that doxycycline has anti-inflammatory properties that block the enzymes involved in the breakdown of joint cartilage. Brown says the study even suggests that doxycycline may protect healthy joints from OA but cautions that further studies are needed in this area.

While uncommon, possible serious side effects of doxycycline include life-threatening allergic reaction, liver damage and irritation of the esophagus, according to the FDA. The FDA also cites common (albeit less serious) side effects including nausea, vomiting, diarrhea and sensitivity of the skin to sunlight.

An Emerging Therapy For Rheumatoid Arthritis
3. Abatacept (Orencia, Bristol-Myers Squibb). The FDA recently approved Orencia for treating moderate to severe rheumatoid arthritis (RA). The FDA approval was based upon the results of three double-blind, randomized phase III trials in which researchers showed that Orencia decreases the symptoms and signs of the autoimmune disease (see “News And Trends,” page 7, January/February issue).

One of the studies, which was published in The New England Journal of Medicine (NEJM) last fall, showed that abatacept had significant clinical and functional benefits for RA patients who had previously had an inadequate response to TNF-a therapy.

After six months, approximately 50 percent of patients in the abatacept group had an ACR 20 response in comparison to 19.5 percent of patients in the placebo group. The study also noted that 20 percent of the patients treated with abatacept achieved an ACR 50 response whereas only 3.8 percent achieved that response in the placebo group.

In a previous “News And Trends” article (see page 8, November/December 2005 issue), Mark Genovese, MD, the lead author of the NEJM study, cited the unique mechanism of abatacept.

“Abatacept is an entirely different class of medication,” noted Dr. Genovese, an Associate Professor of Medicine in the Division of Immunology and Rheumatology at the Stanford University School of Medicine. “As a selective costimulation modulator, it interferes with a signaling process between certain cell types in the immune system. As such, it can block initiation and stimulation of T-cells, which are important in the initiation and perpetuation of rheumatoid arthritis.”

Dr. Genovese says abatacept is a “significant” addition to the armamentarium for RA, particularly when it comes to patients who have had an inadequate response to TNF-a inhibitors.

In his experience, Dr. Genovese has found that abatacept has few side effects, which range from headache to nausea. He notes that some patients in the study had other adverse events including upper respiratory tract infection.

Additionally, Dr. Genovese says the use of infusion therapy facilitates patient compliance with treatment.

A Rising Therapeutic Option For Psoriatic Arthritis And RA
4. Adalimumab (Humira, Abbott). Last fall, adalimumab garnered two new FDA-approved indications (see page 9, “News And Trends,” November/ December 2005 issue). Clinicians can now use the drug to treat the signs and symptoms of active arthritis in patients with psoriatic arthritis (PsA). One can also use adalimumab as a first-line treatment for the recent onset of moderate to severe RA.

(Photo courtesy of the American College of Rheumatology)

These bilateral X-rays are consistent with psoriatic arthritis (PsA). Adalimumab has been approved by the FDA for treating the signs of symptoms of PsA. The medication has also been approved as a first-line treatment for moderate to severe rheumatoid arthritis (RA).

Brian Peck, MD, an Assistant Clinical Professor of Medicine at the Yale University School of Medicine, says early, aggressive treatment of RA is critical to delaying or avoiding joint destruction and maintaining function. Accordingly, he says adalimumab’s expanded indication for the first-line treatment of RA is a key milestone.
“The formal FDA approval for TNF-a inhibitors as a first-line therapy for RA is significant in that it will encourage the use of these drugs at earlier disease stages,” noted Dr. Peck in a previous “News And Trends” article (see page 9, November/December 2005 issue).

Philip Mease, MD, calls adalimumab a “welcome addition” to the current modalities used to treat PsA and RA. Dr. Mease, who is a Clinical Professor in the Department of Medicine at the University of Washington and is in private practice in Seattle, notes he has had two years of experience with adalimumab and has seen a very good patient response.

The expanded indication for RA was based upon a two-year study of nearly 800 patients with active recent onset of moderate to severe RA. According to the study, 62 percent of patients on a combination of adalimumab and methotrexate achieved an ACR 50 response whereas 46 percent of patients on methotrexate alone and 41 percent of those on adalimumab alone achieved the ACR 50 response.

Adalimumab’s psoriatic arthritis indication was based upon results from the ADEPT trial. Researchers of the trial, which involved more than 300 patients, found that patients who received adalimumab had significantly greater improvement in joint and skin disease symptoms than the placebo group. Nearly 70 of these patients had skin lesions that comprised over three percent of their body surface area. Approximately 75 percent of this subgroup of patients achieved a PASI 50 response with adalimumab at six months.

Nathan Wei, MD, a Fellow of the American College of Rheumatologists, says he had an “overwhelmingly positive” experience using adalimumab to treat PsA. He notes that he had used the drug off-label to treat the condition prior to the drug gaining FDA approval for the indication.

“The skin response is the most dramatic change in these patients,” offered Dr. Wei in the aforementioned “News And Trends” article.

In terms of potential drawbacks, Dr. Mease notes that injections of adalimumab can be expensive. According to the manufacturer of adalimumab, potential side effects may include headaches, rashes, injection site reactions and upper respiratory and sinus infections. If infections occur, Dr. Mease says clinicians should cease using adalimumab until the infection clears.

Can A New B-Cell Targeted Therapy Have An Impact On RA?
5. Rituximab (Rituxan, Genentech). Completing the wave of drugs to recently gain a FDA-approved indication for RA is rituximab. In addition to the studies that precipitated the new indication for rituximab (see page 6, “News And Trends”), Paul Emery, MD, FRCOP, notes that he has five years of experience with the drug and has treated more than 100 RA patients with rituximab.

The medication has a unique mode of action in that it depletes CD20 positive B-cells, which contribute to the development of RA, according to Dr. Emery, an Arc Professor of Rheumatology and Head of the Academic Unit of Musculoskeletal Disease at the University of Leeds in the United Kingdom.

Dr. Emery notes that this therapy requires B-cell depletion for its action. Accordingly, as patients are treated for this chronic disease, they will be without their B-cells long-term. Dr. Emery says this has not caused major problems but follow-up so far remains relatively short for such a chronic, lifelong disease.

Rituximab was recently approved by the FDA for treating moderate to severe RA. The medication has a unique mode of action in that it depletes CD20 positive B-cells, which contribute to the development of the disease, according to Paul Emery, MD, FRCOP, an Arc Professor of Rheumatology at the University of Leeds in the United Kingdom.

In terms of potential drawbacks, rituximab can be an expensive treatment and most insurance companies will not pay for it, according to Dr. Peck, the Medical Director of the Arthritis Center of Connecticut in Waterbury, Ct.

Other issues to look out for are minor injection and infusion reactions, notes Dr. Peck. Other possible adverse side effects for rituximab include tumor lysis syndrome, mucocutaneous reactions, cardiac arrhythmias and hypersensitivity reactions, according to the drug’s manufacturer Genentech.

Rituximab previously received FDA approval for the treatment of relapsed or refractory, low-grade or follicular CD-20 positive B-cell non-Hodgkin’s lymphoma.

Better Compliance For Osteoporosis Treatment?
6. Ibandronate sodium (Boniva, Roche). Given that more than 40 million Americans over the age of 50 are either affected by osteoporosis or considered at risk for the condition, the emergence of the once-a-month pill Boniva has been viewed as a significant advance.

The monthly dosage of 150 mg was approved by the FDA in March of 2005 for the treatment of postmenopausal osteoporosis. The FDA approval was based upon results from the MOBILE study, a multinational, randomized, double-blind trial of approximately 1,600 women with postmenopausal osteoporosis. The study found that the monthly dose of Boniva was equivalent to the daily dose of Boniva (2.5 mg) in increasing bone mineral density at the lumbar spine and other skeletal sites after one year of treatment.

More recently, the “Boniva Alendronate Trial In Osteoporosis” study found that approximately 66.1 percent of 342 postmenopausal women with osteoporosis preferred Boniva to alendronate (Fosamax, Merck). (See page 7, “News And Trends,” March issue.) Ronald Emkey, MD, the lead author of the study, notes the less frequent dosing of Boniva may help facilitate greater patient compliance for longer periods of time.

“There were no real surprises in the study as patients tend to favor less frequent dosing. This is possible as ibandronate) is a very potent bisphosphonate,” noted Dr. Emkey in the aforementioned “News And Trends” article.

Dr. Emkey, the Medical Director of Radiant Research in Reading, Pa., notes that possible side effects of Boniva include back pain, upper respiratory infection and dyspepsia. He advises that patients stand or sit upright when taking the medication and take the medication only with water at least an hour before eating or drinking.

For those patients who may have difficulty with those dosing requirements, an injectable formulation of Boniva for quarterly administration by clinicians was approved by the FDA in January.

Is There A Viable Alternative To Allopurinol For Gout?
7. Febuxostat (TAP Pharmaceutical Products Inc.). While febuxostat has not received FDA approval yet, two studies have shown that the medication is a promising modality for reducing hyperuricemia.

One study, which was presented at the ACR Annual Scientific Meeting in November, assessed more than 1,000 patients over a 28-week period. According to the study, 48 percent of those treated with 80 mg/day of febuxostat achieved a reduction of their uric acid level to less than 6 mg/dL at the last three monthly visits. In comparison, only 22 percent of the group taking allopurinol achieved that uric acid level reduction and none of the placebo treatment group achieved the reduction.

A subsequent randomized study, published in The New England Journal Of Medicine, assessed more than 700 patients with gout and serum uric acid levels of at least 8 mg/dL. According to the study, more than 50 percent of patients taking 80 mg/day of febuxostat and 62 percent of those taking 120 mg/day of febuxostat achieved a serum uric acid level of less than 6 mg/dL at the last three monthly visits. In comparison, only 21 percent of patients treated with 300 mg/day of allopurinol reached this target.

“(Febuxostat) distinguishes itself from allopurinol in that it is metabolized by the liver rather than being solely reliant on renal excretion,” notes Joan McTigue, MS, PA-C, who is affiliated with the Division of Rheumatology at the University of Florida College of Medicine.

McTigue adds that febuxostat appears to be safer in patients who have impaired renal function, which is a frequent comorbid condition in patients with gout. However, she notes that further research is needed in order to adequately compare the safety of the two drugs. She also cautions that the side effects of febuxostat, which is currently being reviewed by the FDA, are presently unknown.

McTigue says the great advantage of febuxostat is it will not require renal dosing, noting that many people with gout have chronic renal insuffiency.

Can These Medications Help Relieve Fibromyalgia Pain?
8. Pregabalin (Lyrica, Pfizer Inc.). While Lyrica is known and FDA-approved for the indications of diabetic peripheral neuropathy and postherpetic neuralgia, the drug may have potential utility in treating pain associated with fibromyalgia, according to Kim Dupree Jones, RN, PhD, FNP.

“We have tested Lyrica and it allows people with fibromyalgia-related pain to take less narcotic pain medications and still get good symptom relief,” claims Dr. Jones, an Assistant Professor at the School of Nursing at Oregon Health and Science University.

Dr. Jones also cites a study that was published in the April 2005 issue of Arthritis and Rheumatism that looked at pregabalin and its effects on fibromyalgia. The randomized, double-blinded trial assessed more than 500 patients with fibromyalgia and found that 450 mg/day of pregabalin “significantly reduced the average severity of pain” in these patients. The authors of the study also noted that dosages of 300 and 450 mg/day of pregabalin facilitated improvements in fatigue and sleep quality as well.

While pregabalin is not FDA-approved for fibromyalgia pain, a randomized, double-blinded trial of over 500 patients with fibromyalgia found that 450 mg/day of pregabalin led to a significant reduction of pain.

Dr. Jones notes that research is still being conducted on pregabalin since the FDA has not currently approved it for the treatment of fibromyalgia.

Reported side effects of pregabalin include weight gain, dizziness, blurry vision, trouble concentrating, swelling in the hands and feet, dry mouth and sleepiness. Dr. Jones also emphasizes the importance of light exercising in order to reduce the necessary dosage of pregabalin.

9. Tramadol (Ultram, Ortho-McNeil Pharmaceuticals). While current studies evaluating the effectiveness of Ultram for fibromyalgia pain are ongoing, Dr. Jones has found in her clinical experience that Ultram is a first line treatment for pain associated with the chronic condition.

Dr. Jones, who maintains a weekly level V referral practice in diagnosing and treating fibromyalgia, notes she was involved in a previous randomized controlled trial that assessed the efficacy of Ultram for patients with fibromyalgia. She notes that Ultram works well for fibromyalgia patients who have mild to moderate pain and discomfort. Dr. Jones adds that patients usually respond to the medication in less than an hour.

In her clinical experience, Kim Dupree Jones, RN, PhD, FNP, has found that Ultram works well for fibromyalgia patients who have mild to moderate pain and discomfort.

Dr. Jones also cites a study on tramadol that was published in an October 2000 issue of the Journal of Clinical Rheumatology. The double-blind study, which assessed 69 patients over a six-week period, found that tramadol was effective in reducing “the severity of pain among fibromyalgia syndrome patients” and the mean pain intensity scores were lower than the control group.

Some potential adverse effects of Ultram include seizure risks, dizziness and nausea among other symptoms.

10. Tramadol hydrochloride and acetaminophen (Ultracet, Ortho-McNeil Pharmaceuticals). When looking for a medication to help alleviate a patient’s discomfort and pain from fibromyalgia, Dr. Jones says she commonly prescribes Ultracet.

She cites the results from a multicenter, double-blind study of more than 300 patients that evaluated the efficacy of Ultracet among patients with fibromyalgia pain. The study, which was published in the May 2003 issue of The American Journal of Medicine, found that patients treated with Ultracet experienced more pain relief and improved physical function than those in the placebo group.

A multicenter, double-blind study of more than 300 fibromyalgia patients shows that Ultracet reduces pain and improves physical function in these patients.

In a randomized, controlled trial that Dr. Jones was involved with nearly 10 years ago, she notes that Ultracet worked well for mild to moderate fibromyalgia pain. In her experience treating patients with fibromyalgia, Dr. Jones has found little adverse drug-drug interactions with Ultracet.

Some noted side effects of Ultracet are seizure risks, tiredness and constipation. Dr. Jones adds that patients who are just starting to take the medication may experience nausea.

“Ultracet causes nausea at first so the patient may want to buy a pill splitter and slowly work up to an ideal dose,” suggests Dr. Jones, who adds that the highest recommended dosage is eight tablets in 24 hours.