Catherine A Heyneman

Oral versus Topical NSAIDs in Rheumatic Diseases A Comparison

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide and are responsible for approximately one-quarter of all adverse drug reaction reports. NSAIDs are widely prescribed for patients with rheumatic disease — a population at increased risk for serious gastrointestinal (GI) complications. Topical administration of NSAIDs offers the advantage of local, enhanced drug delivery to affected tissues with a reduced incidence of systemic adverse effects, such as peptic ulcer disease and GI haemorrhage.NSAIDs administered topically penetrate slowly and in small quantities into the systemic circulation; bioavailability and maximal plasma NSAID concentration after topical application are generally less than 5 and 15%, respectively, compared with equivalent oral administration. Product formulation may have a dramatic impact, not only on absorption rates but also on penetration depth. Compared with oral administration, topical application leads to relatively high NSAID concentrations in the dermis. Concentrations achieved in the muscle tissue below the site of application are variable, but are at least equivalent to that obtained with oral administration. NSAIDs applied topically do reach the synovial fluid, but the extent and mechanism (topical penetration versus distribution via the systemic circulation) remain to be determined. In addition, marked interindividual variability was noted in all studies; percutaneous absorption may be strongly influenced by individual skin properties.In general, interpretation of clinical studies measuring efficacy of topical NSAIDs in rheumatic disease states is difficult because of a remarkably high placebo response rate, use of rescue paracetamol (acetaminophen), and significant variability in percutaneous absorption and response rates between patients. Overall efficacy rates attributable to topical NSAIDs in patients with rheumatic disorders ranged from 18 to 92% of treated patients. Topically applied NSAIDs have a superior safety profile to oral formulations. Adverse effects secondary to topical NSAID application occur in approximately 10 to 15% of patients and are primarily cutaneous in nature (rash and pruritus at site of application). GI adverse drug reactions are rare with topically applied NSAIDs, compared with a 15% incidence reported for oral NSAIDs. Available clinical studies suggest, but do not document, equivalent efficacy of topical over oral NSAIDs in rheumatic diseases.

Zinc Deficiency and Taste Disorders

Elemental zinc supplementation in daily dosages of 25-100 mg po appears to be an efficacious treatment for taste dysfunction secondary to zinc depletion. Insufficient evidence is available to determine the efficacy of zinc supplementation for the treatment of hypogeusia or dysgeusia secondary to drug therapy or medical conditions that do not involve low serum zinc concentrations.

Topical phenytoin treatment of stage II decubitus ulcers in the elderly.

OBJECTIVE: To compare the healing of stage II decubitus ulcers with topically applied phenytoin sodium with two other standard topical treatment procedures in a long-term care setting; and to assess the extent of systemic absorption after topical application in the phenytoin group. METHODS: Forty-seven nursing home patients with stage II decubitus ulcers were chosen for this study. The patients were matched for age, gender, and size and severity of wounds, and randomly assigned to each treatment group. Clinical assessment of decubitus ulcers was performed at the beginning of treatment and at each dressing change. Ulcers were examined for the presence of healthy granulation tissue, reduction in surface dimensions, and time to healing. Two phenytoin sodium plasma concentrations were to be obtained on all patients in the phenytoin group. RESULTS: Topical phenytoin therapy resulted in a shorter time to complete healing and formation of granulation tissue when compared with DuoDerm dressings or triple antibiotic ointment applications (p ⩽ 0.05). The mean ± SD time to healing in the phenytoin group was 35.3 ± 14.3 days compared with 51.8 ± 19.6 and 53.8 ± 8.5 days for the DuoDerm and triple antibiotic ointment groups, respectively. Healthy granulation tissue in the phenytoin group appeared within two to seven days in all subjects. Patients in the standard treatment groups required six to 21 days to produce new granulation tissue. Serum phenytoin sodium concentrations were nondetectable. No patient withdrew from the study secondary to adverse treatment effects. CONCLUSIONS: Both the phenytoin and standard treatment groups showed progress over the study period. However, the phenytoin group demonstrated more rapid results in all aspects of ulcer healing.

Calcitonin in phantom limb pain.

PLP is a challenging disorder that is often difficult to treat. Like all other types of pain, PLP is a tremendous source of morbidity and should be treated aggressively. Though evidence is very limited, one or two doses of intravenous salmon calcitonin 200 IU may be an effective treatment. The minor adverse effects reported in the literature would seem to indicate the relative safety of this regimen; however, clinicians should be aware of the rare but severe hypersensitivity reactions that can occur with salmon calcitonin. Intranasal calcitonin appears to be similar in efficacy to the parenteral formulation, at least in pain associated with vertebral crush fractures. Long-term studies using intranasal calcitonin for relief of PLP are warranted given the ease of administration of this dosage form.

Nephrotoxic Potential of Selective Cyclooxygenase-2 Inhibitors

OBJECTIVE To determine the relative nephrotoxic potential of cyclooxygenase (COX)-2 inhibitors. DATA SOURCES A MEDLINE search (1996—February 2004) identified clinical trials evaluating the nephrotoxicity of COX-2 inhibitors versus traditional nonsteroidal antiinflammatory drugs (NSAIDs). Key search terms included cyclooxygenase inhibitors, nonsteroidal antiinflammatory agents, nephrotoxicity, and chemically induced. DATA SYNTHESIS Three clinical trials determined that COX-2 inhibitors have similar adverse effects on the kidney when compared with nonselective NSAIDs, while 2 studies concluded that COX-2 inhibitors are less nephrotoxic than nonselective NSAIDs. All 5 trials utilized low numbers of subjects, short-term therapy, and surrogate markers of kidney damage. CONCLUSIONS COX-2 inhibitors may not offer distinct advantages over nonselective NSAIDs with respect to kidney function. Longer trials in patients with comorbidities are warranted. These agents should be used cautiously or not at all in patients with predisposing conditions.

Treatment and Prevention of Otitis Media

OBJECTIVE: To review and summarize recent advances in the treatment and prevention of otitis media (OM). DATA SOURCES: A MEDLINE search (1996–March 2000) was performed to identify relevant primary and review articles. References from these articles were also reviewed if deemed important. STUDY SELECTION AND DATA EXTRACTION: English-language primary and review articles focusing on the treatment and prevention of acute otitis media (AOM) were included. Studies focusing exclusively on OM with effusion or serous OM and chronic suppurative OM were excluded. Information regarding prevention and drug therapy was reviewed, with an emphasis placed on advances made in the last two years. DATA SYNTHESIS: Recently, an expert panel of the Centers for Disease Control and Prevention recommended use of only three of 16 systemic antibiotics approved by the Food and Drug Administration for treatment of AOM: amoxicillin, cefuroxime axetil, and ceftriaxone. Controversy exists over the importance of key selection factors used by the expert panel in determining which antibiotics to recommend in a two-step treatment algorithm, that is, in vitro data, pharmacodynamic profiles, and necessity for coverage of drug-resistant Streptococcus pneumoniaeat all steps of empiric treatment. Additional antibiotic and patient selection factors useful for individualizing therapy include clinical efficacy, adverse effects, frequency and duration of administration, taste, cost, comorbid infections, and ramifications should bacterial resistance develop to the chosen antibiotic. Presumed or past patient/caregiver adherence (especially when antibiotic failure has occurred) is also paramount in selecting antibiotic therapy. A three-step treatment algorithm for refractory AOM that employs amoxicillin, trimethoprim/sulfamethoxazole (TMP/SMX), or high-dose amoxicillin/ clavulanate (depending on the prior dose of and adherence to amoxicillin therapy), and ceftriaxone or tympanocentesis at steps 1, 2, and 3, respectively, appears rational and cost-effective. The recent upsurge in antimicrobial resistance is highlighted, and recommendations are presented for the treatment of AOM and prevention of recurrent otitis media (rAOM). CONCLUSIONS: Amoxicillin remains the antibiotic of choice for initial empiric treatment of AOM, although the traditional dosage should be increased in patients at risk for drug-resistant S. pneumoniae. In cases refractory to high-dose amoxicillin, TMP/SMX should be prescribed if adherence to prior therapy seemed good or complete, or high-dose amoxicillin/clavulanate if adherence was incomplete or questionable. Ceftriaxone should be reserved as third-line treatment. The increasing prevalence of drug-resistant S. pneumoniaeemphasizes the importance of alternative medical approaches for the prevention of OM, as well as judicious antibiotic use in established cases. Removal of modifiable risk factors should be first-line therapy for prevention of rAOM. We support the use of conjugate pneumococcal vaccine per guidelines for prevention of rAOM from the Advisory Committee on Immunization Practice of the Centers for Disease Control and Prevention, with consideration given to influenza vaccine for cases of rAOM that historically worsen during the flu season. Sulfisoxazole prophylaxis should be reserved for children who are immunocompromised, have concurrent disease states exacerbated by AOM, or meet the criteria of rAOM despite conjugate pneumococcal and influenza vaccination. Therapy should be intermittent, beginning at the first sign of an upper respiratory infection, and should continue for 10 days. The invasive nature and risks of anesthesia relegate myringotomy, tympanostomy tubes, and adenoidectomy to last-line therapies for rAOM.

Conjugated Heptavalent Pneumococcal Vaccine

OBJECTIVE: To review the immunogenicity, efficacy, and safety of the heptavalent conjugated pneumococcal vaccine (PCV7). DATA SOURCES: A MEDLINE search (1993–August 2001) of research limited to humans published in the English language was conducted. STUDY SELECTION: Findings from randomized, controlled, multicenter trials were reviewed. Literature regarding epidemiology, control, and treatment of invasive pneumococcal diseases in different populations and the Advisory Committee on Immunization Practices recommendations were also reviewed. DATA SYNTHESIS: PCV7 administered to infants aged 2, 4, and 6 months, with a booster dose at 12–15 months, has been shown to be immunogenic. It decreases the incidence of invasive pneumococcal disease; individual data on bacteremia and meningitis are unavailable. Findings from clinical trials showed that invasive pneumococcal disease caused by vaccine serotypes was reduced by 87%, 58%, and 62% for children <1 year, <2 years, and <5 years of age, respectively, after introduction of routine vaccine use. The overall incidence of acute otitis media did not decrease significantly. However, culture-confirmed episodes and episodes due to pneumococcal serotypes included in the vaccine were reduced. The vaccine was immunogenic in children with sickle cell disease, but its efficacy in preventing invasive pneumococcal diseases remains unclear. Although immunogenicity and efficacy trials are lacking, the vaccine is recommended for Alaskan Native or American Indian children between 24 and 59 months of age, and for children with underlying conditions such as HIV infection, AIDS, other immunocompromising conditions, and chronic illnesses. At the manufacturers list price of

Intravenous immune globulin for inducing remissions in systemic lupus erythematosus.

58/dose, PCV7 is not projected to be cost-effective after 4 doses. Postmarketing analysis evaluating immunogenicity and efficacy in the excluded population may favorably change this. CONCLUSIONS: Based on published efficacy and immunogenicity data, pharmacy formularies should include PCV7.

Fluticasone versus Salmeterol/Low-Dose Fluticasone for Long-Term Asthma Control

The evidence supporting the use of long-term IVIG therapy to induce remissions in SLE is unimpressive. The single extant clinical study used an open-label design with 12 patients, no placebo control, and questionable statistical methodology. The lack of definitive clinical studies, however, is tempered by case reports documenting significant improvement and apparent lack of toxicity in patients with SLE treated with IVIG. Standard first-line therapy of active SLE should consist of nonsteroidal antiinflammatory drugs, followed by low-dose corticosteroids and antimalarial compounds. Second-line therapeutic alternatives are the cytotoxic agents methotrexate, azathioprine, or cyclophosphamide. IVIGs primary advantage over these conventional therapies is that, unlike immunosuppressant and cytotoxic drugs, IVIG has not been reported to increase the risk of opportunistic infections. Additionally, IVIG obviates the ovarian/testicular toxicity, hemorrhagic cystitis, and carcinogenicity caused by cyclophosphamide. However, IVIG therapy is extremely expensive. (Approximate average wholesale price is

Glucosamine for Osteoarthritis: Cure or Conundrum?

1800 per dose for a 70-kg patient). Thus, IVIG treatment consisting of 0.4 g/kg/d for 5 consecutive days on a monthly basis should be reserved for patients with active SLE resistant to the first- and second-line therapies. While IVIG-induced acute renal failure is considered rare, the serious nature of this adverse event warrants close monitoring of blood urea nitrogen and serum creatinine during and several days after treatment. Preexisting renal dysfunction should be considered a relative contradiction. Further double-blind multicenter trials are warranted to determine the long-term safety, efficacy, and cost/benefit ratio of using IVIG in SLE.