American Pain Society (APS) 30th Annual Scientific Meeting

May 19-21, 2011; Austin, TX
_____________________________________

Poster

Meta-analysis Reports Low Rate of Cardiovascular and Gastrointestinal Events With Diclofenac Gels

Austin, TX—A post hoc analysis of clinical trials involving diclofenac sodium 1% gel (DSG) or diclofenac diethylamine 1.16% gel (DEG) examined the topical agents’ cardiovascular and gastrointestinal (GI) safety in patients with osteoarthritis (OA) of the hand or knee. Data were presented in a poster session at the APS annual meeting.

A multinational research team pooled data from five randomized, placebo-controlled trials comparing DSG with placebo and examined data from a 1-year open-label study of DSG and two 3-week trials investigating DEG. The placebo-controlled trials enrolled a cumulative 2209 patients aged ≥35 years with OA of the knee and aged ≥40 years with OA of the hand; all had mild to moderate disease. Patients were randomized to DSG (n = 1121) or placebo (n = 1088), with knee patients applying 4 g of gel four times daily for 12 weeks and hand patients using 2 g four times daily for 8 weeks.

In the DSG arm, 569 patients (50.8%) experienced an adverse event, of which 1.4% was serious. Adverse events occurred in 479 patients (44.0%) given placebo, of which 0.8% were serious.

Similar proportions of patients in the DSG arm and the placebo group had a GI adverse event (5.1% vs 4.4%, respectively) or a cardiovascular one (1.4% vs 1.0%, respectively). In the DSG and placebo groups, most GI events fell into the “other” category (2.1% vs 2.4%, respectively), which encompassed various ailments of the upper and lower GI tract, such as abdominal distension and masses, anal fissures, colonic polyps, hemorrhoids, mouth ulcers, tongue disorders, and dysphagia. The second most common GI event was diarrhea, experienced by 10 patients (0.9%) treated with DSG and 11 patients (1.0%) taking placebo. Worsening hypertension was the only cardiovascular event to affect more than 0.1% of patients, observed in 10 (0.9%) using DSG and 7 (0.6%) taking placebo.

The open label study (n = 578) required participants to apply 4 g of DSG four times daily to OA-afflicted knees for 12 months. Three-quarters of patients (435) experienced an adverse event, but only 112 cases (19.4%) were considered treatment-related. The most common GI events were nausea, gastroenteritis, and hiatal hernia, each occurring in one patient. No one had a cardiovascular event or a serious treatment-related adverse event.

One DEG trial randomized 238 patients with knee OA to DEG (n = 117) or to placebo (n = 121) for 3 weeks. The adverse event rate was approximately 9% in each arm, with two GI events in the placebo group and none in the treatment arm and no treatment-related cardiovascular events in either group. The remaining trial compared 3 weeks of DEG use (n = 165) with 400 mg of oral ibuprofen (n = 156) use in patients with hand OA.

No serious treatment-related adverse events were reported. Ibuprofen was more likely than DEG to cause a GI event (14.1% vs 9.1%, respectively). Nausea and abdominal discomfort were the most common GI events associated with ibuprofen use, each experienced by 3.8% of patients. Only 0.6% of DEG-treated patients suffered nausea and 1.8% reported abdominal discomfort. Upper abdominal pain was the most common GI adverse event in the DEG group, affecting 2.4% of patients compared with 2.6% given placebo. The DEG and ibuprofen arms had similar cardiovascular event rates (1.8% vs 1.3%, respectively).

Cumulatively, the studies showed that DEG and DSG are well tolerated by patients with OA of the hand or knee. Although GI and cardiovascular adverse events are a concern with regular use of nonsteroidal anti-inflammatory drugs, the authors said that they were “infrequent and rarely related to treatment” with diclofenac. They noted that “only one serious treatment-related adverse event was reported in a population of >1500 patients who received topical diclofenac.”

Endo Pharmaceuticals funded the study.
________________________________________________________________________________________________

Poster

Capsaicin 8% Patch Safe for Managing Postherpetic Neuralgia in the Elderly

Austin, TX—Herpes zoster—more commonly known as shingles—is a painful, blistering skin rash that occurs with reactivation of the varicella-zoster virus (VZV). VZV is the same virus that causes chickenpox; once the initial infection subsides, the virus remains dormant in the body only to re-emerge as shingles in some individuals, particularly those who are aged or immunocompromised. Although herpes zoster can strike at any age, 50% of cases occur in people >85 years of age.

Recovery from herpes zoster generally takes 2 to 4 weeks. Advanced age, however, correlates with an increased risk of long-term complications. Among elderly patients, postherpetic neuralgia (PHN) is the most prevalent of these. PHN is a debilitating condition characterized by persistent pain and can last for months or years after a herpes zoster rash has cleared. It has been reported that 21% of individuals aged 80 to 84 years develop PHN from shingles.

The side-effect profiles of many analgesic treatments make them unsuitable for treating PHN-related pain in elderly patients, whereas others are ineffective. As a result, clinicians have few options for treating PHN in those that it is most likely to affect.

In a poster session at the APS annual meeting, researchers presented a meta-analysis of data from four trials that confirmed the safety and efficacy of NGX-4010 in elderly individuals with PHN. They reported that a single 60-minute application of the dermal 8% capsaicin patch provided patients with significant pain relief, lasting as long as 12 weeks in some cases.

Capsaicin is the compound that imbues various hot peppers with their fieriness and is a potent agonist of the transient receptor potential vanilloid 1 (TRPV1), which is involved in transmitting the sensation of pain. Capsaicin targets and binds to TRPV1, causing a reversible reduction in the density of epidermal nerve fibers and inhibiting the ability of the nociceptors to transmit pain signals.

All four multicenter, double-blind trials enrolled adults who had been experiencing PHN symptoms for at least 3 months and randomized them to receive NGX-4010 or low-dose capsaicin (0.04%) for 12 weeks. Patients were permitted to take concomitant oral pain medications provided they remained on a fixed dose that was already being used prior to study participation; use of topical analgesics during the study was not permitted.

With the goal of assessing the effects of NGX-4010 on elderly patients, the poster’s investigators restricted their analyses to 305 patients aged ≥73 years (mean age, 80 years) exposed to the NGX-4010 patch once for 60 minutes and 277 patients exposed to the low-dose capsaicin patch for 30-, 60-, or 90-minute intervals.

The majority of patients had suffered from PHN for ≥6 months. At baseline, they were asked to rate their pain for the previous 24 hours from 0 to 10 on the Numeric Pain Rating Scale (NPRS), with 0 indicating no pain and 10 correlating with the worst pain imaginable. Initial NPRS scores ranged from 3 to 9. The test was repeated at 8 weeks and 12 weeks, when the study concluded.

From week 2 to week 8, the patients treated with NGX-4010 experienced a greater mean reduction in NPRS scores compared with patients given low-dose capsaicin (25.8% vs 17.1%, respectively; P = .0005). The NGX-4010 group also experienced a greater mean reduction than the low-dose capsaicin arm from week 2 to week 12 (25.6% vs 17.0%, respectively; P = .0009). In addition, more patients receiving NGX-4010 than patients receiving low-dose capsaicin were deemed responders, which was one of the study’s secondary end points.

NGX-4010 also had a good safety profile, with most adverse events self-limited or of mild to moderate intensity. The most common adverse events related to use of NGX-4010 were erythema (52.0%), pain (33.3%), pruritus (5.1%), and papules (6.7%) at the application site, and 5.3% of patients experienced nausea.

In a related study of NGX-4010, also presented in a poster session at the APS annual meeting, researchers reported results from a Neuropathic Pain Questionnaire (NPQ) that had been completed by 384 patients before and after treatment with a single 60-minute application of NGX-4010 and 327 patients who received a low-dose control patch of capsaicin for 30, 60, or 90 minutes. On the NPQ, patients were asked to rate their experience with the following types of pain: burning pain, sensitivity to touch, shooting pain, numbness, electric pain, tingling pain, squeezing pain, and freezing pain. They were also asked how unpleasant and overwhelming their usual pain was and whether their pain increased when touched or with changes in the weather. The survey was completed after enrollment and repeated at week 12, which marked the end of the study.

At week 12, the researchers found that patients who had been treated with NGX-4010 demonstrated greater improvement from baseline on almost all NPQ measures compared with the low-dose capsaicin group. However, the reduction in pain per NPQ measures between screening and week 12 only reached statistical significance in the categories of burning pain, shooting pain, and numbness. Although more patients in the NGX-4010 group than in the low-dose capsaicin group achieved complete resolution of almost all NPQ criteria, statistical significance was only achieved in the measures of burning pain and tingling.

Based on these findings, the investigators concluded that NGX-4010 is a viable treatment option for elderly patients with PHN. They also noted the need for further studies, stating that “the differential effect of NGX-4010 on several components of the NPQ may guide further studies on pathophysiology and treatment of pain associated with PHN.”

Both studies reviewed were sponsored by NeurogesX.