American Pain Society (APS) 30th Annual Scientific Meeting
May 19-21, 2011; Austin, TX
Capsaicin 8% Patch Safe for Managing Postherpetic Neuralgia in the Elderly
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. Studies suggest that 21% of shingles sufferers 80 to 84 years of age develop PHN.
The side effects profile of many analgesic treatments make them unsuitable for treating PHN-related pain in elderly patients and other agents are ineffective. Thus, clinicians have few options for treating PHN in those it is most likely to affect.
In a poster session at the American Pain Society (APS) 30th 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 up to 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 12-week study was not permitted.
With the goal of assessing the effects of NGX-4010 on elderly patients, the poster’s investigators restricted their analysis to 305 patients aged ³73 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 or longer. 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 weeks 8 and week 12, when the study concluded.
From week 2 to week 8, the patients who were treated with NGX-4010 experienced a greater mean reduction in NPRS scores compared with the patients given low-dose capsaicin (25.8% vs 17.1%, respectively; P=.0005). The NGX-4010 group also experienced a greater mean reduction in pain 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 endpoints.
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%), pruritis (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 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 by 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, patients who had been treated with NGX-4010 experienced 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 reached statistical significance only for 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 on almost all NPQ end points assessed, statistical significance was achieved only on 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 were sponsored by NeurogesX.
Meta-analysis Reports Low Rate of Cardiovascular and Gastrointestinal Events With Diclofenac Gels
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 30th Annual Meeting of the American Pain Society.
A multinational research team pooled data from five previously conducted randomized, placebo-controlled trials that compared DSG use with placebo. The investigators also 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 ³35 years with OA of the knee and aged ³40 years with OA of the hand; all had mild to moderate disease. Patients were randomized to receive DSG (n=1121) or placebo (n=1088), with the patients having OA of the knee applying 4 g of gel four times daily for 12 weeks and the patients with OA of the hand administering 2 g of the gel to each hand 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%) who were given placebo, of which 0.8% of these were serious.
Similar proportions of patients in the DSG arm and the placebo group experienced a GI (5.1% vs 4.4%, respectively) or cardiovascular (1.4% vs 1.0%, respectively) adverse event. In the DSG and placebo groups, most GI events fell into the “other” category (2.1% vs 2.4%, respectively), which encompassed various ailments affecting 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, which was reported by 10 patients (0.9%) who were treated with DSG and 11 (1.0%) who were assigned to placebo. Worsening hypertension was the only cardiovascular event to affect >0.1% of patients, and it was observed in 10 (0.9%) patients using DSG and 7 (0.6%) receiving placebo.
The open-label clinical study (n=578) required participants to apply 4g of DSG four times daily to OA-afflicted knees for 12 months. Three-quarters of patients (435) in the study experienced an adverse event, but only 112 of these cases (19.4%) were considered treatment-related. The most common GI events reported were nausea, gastroenteritis, and hiatal hernia, each of which occurred in one study participant. No one experienced a cardiovascular event or suffered a serious treatment-related adverse event.
One DEG trial recruited 238 patients who had a diagnosis of OA in the knee. Investigators randomized the participants to receive DEG (n=117) or placebo (n=121), which was taken for
3 weeks.
The adverse event rate reached approximately 9% in each study arm, with two patients in the placebo group reporting a GI event compared with no patients in the DEG treatment arm. No patients in either group experienced a cardiovascular event that was considered to be related to treatment.
The remaining trial that was included in the analysis had compared 3 weeks of DEG (n=165) use with 400 mg of oral ibuprofen (n = 156) use in patients who had OA affecting the hand. No serious treatment-related adverse events were reported to have occurred during this study.
Investigators said ibuprofen was more likely than DEG was to cause a GI event (14.1% vs 9.1%, respectively) during the study. Nausea and abdominal discomfort were the most common GI events associated with ibuprofen use, and each of these events was experienced by 3.8% of patients assigned to this group.
Only 0.6% of patients who were randomized to receive DEG experienced nausea; another 1.8% of patients reported developing abdominal discomfort. Upper abdominal pain was the most common GI adverse event observed among patients treated with DEG, but this occurred more frequently in patients given placebo, although the difference between the groups was not statistically significant (2.4% vs 2.6%, respectively). The DEG and ibuprofen arms also reported similar rates of cardiovascular events (1.8% vs 1.3%, respectively).
Cumulatively, the studies included in this meta-analysis showed that DEG and DSG are well tolerated by patients with OA affecting the hands or knees. Although GI and cardiovascular adverse events remain a concern among patients who use nonsteroidal anti-inflammatory drugs routinely, the authors said that studies showed they were “infrequent and rarely related to treatment” with
diclofenac. They noted that “only one serious treatment-related adverse event had been reported in a population of >1500 patients who received topical diclofenac.”
The meta-analysis was sponsored by Endo Pharmaceuticals.
Benefits With Fluoxetine Therapy After Ischemic Stroke
Data from the phase 3 FLAME (Fluoxetine in Motor Recovery of Patients with Acute Ischaemic Stroke) trial demonstrate that starting patients on a 20-mg dose of daily fluoxetine promptly after an ischemic stroke contributes to better recovery of motor function at 3 months. As a result of the improved function, François Chollet, MD, PhD, head of the neurovascular department at Toulouse University Hospital and chief of the Toulouse Institute for Neurosciences in France, said participants taking fluoxetine were also more likely than those given placebo to be independent in activities of daily living at 90 days. Chollet, a lead investigator for the FLAME trial, presented his team’s findings at the American Academy of Neurology meeting.
FLAME’s primary end point was mean change in the Fugl-Meyer motor scale (FMMS) score from baseline to trial conclusion at 90 days. Secondary end points included mean change in National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Montgomery-Åsberg Depression Rating Scale (MADRS) assessments from study outset to completion.
Patients were eligible for the double-blind, placebo-controlled trial if they had experienced a recent acute ischemic stroke resulting in hemiparesia or hemiplegia, producing moderate-to-severe motor deficit as indicated by a score ²55 on the FMMS. Individuals scoring >20 on the NIHSS were excluded, as were those demonstrating residual disability from a prior stroke or with premorbid disability or cognitive deficits serious enough to hinder assessments. Patients with clinical depression or who had received treatment with antidepressants, neuroleptics, or benzodiazepines in the month before randomization were also excluded.
A total of 118 stroke patients from 9 stroke centers across France were enrolled within 5 to 10 days of stroke onset and randomized to fluoxetine 20 mg/day (n=59) or placebo (n=59) for 90 days. Chollet said all patients received standard care from the facility’s inpatient stroke team and physiotherapy. A physiotherapist administered motor function tests at baseline and again at 30 days and 90 days post-randomization. NIHSS, mRS, and MADRS scores were also assessed according to this timeline.
After censoring patients who died or withdrew, the 90-day statistical analysis included data for 56 patients assigned to placebo and 57 to fluoxetine. Chollet said the analysis corrected for differences in baseline characteristics between the groups. Patients in the fluoxetine group tended to be older than those in the placebo arm (mean age, 66.4 vs 62.9 years, respectively), and more patients randomized to fluoxetine than to placebo had had a stroke previously (16.9% vs 6.8%, respectively). Another adjustment was made to account for differences in mean FMMS score at baseline, which was higher in the fluoxetine arm than the placebo arm (17.1±11.7 vs 13.4±8.8, respectively).
Patients treated with fluoxetine demonstrated significant improvement in overall FMMS motor function scores at 3 months. “This is true for the [over]all score and for the upper limb and lower limb part,” Chollet said. The fluoxetine group had an adjusted mean gain of 34.0 points (95% confidence interval [CI], 29.7-38.4) in overall FMMS scores compared with 24.3 points (95% CI, 19.9-28.7) in the placebo arm (P=.003). FMMS scores reflected a mean gain of 22.9 points (95% CI, 18.6-27.1) in upper limb motor function with fluoxetine compared with 13.1 points (95% CI, 8.9-17.4) with placebo (P=.002); patients recovered slightly less lower limb motor function, with a mean increase of 12.8 points (95% CI, 11.1-14.5) in the fluoxetine group versus 9.5 points (95% CI, 7.8-11.2) in the placebo arm (P=.010).
Minimal difference in total NIHSS scores was observed between the fluoxetine and placebo groups at 90 days (5.8 vs 6.9, respectively). “However, if we look at the motor items of the NIHSS, there is a statistically significant difference in favor of fluoxetine,” Chollet said. Patients treated with fluoxetine had a mean motor score on the NIHSS of 4.7 compared with 6.3 for patients given placebo (P=.012).
Investigators found no significant difference in MADRS scores between the groups, although the adjusted mean change slightly favored fluoxetine over placebo (-0.1 vs +3.2, respectively; P=.032). Researchers identified 17 patients in the placebo group as clinically depressed compared with 4 patients in the fluoxetine group (P=.002), and Chollet said this might suggest that fluoxetine protects against depression.
Fluoxetine was also associated with improvement in mRS scores. “If we look at Rankin score 1 or 2, which means the patient is independent in daily living activities, the number of patients independent is higher—significantly higher—in the fluoxetine group than in the placebo group,” said Chollet, noting that 26.3% of patients given fluoxetine had an mRS score of 0 to 2 compared with only 8.9% of patients taking placebo (P=.015).
Rates of serious adverse events were low, and Chollet said fluoxetine was well tolerated. Of the most common adverse events, nausea, diarrhea, and partial seizure were more prevalent among fluoxetine users; whereas a greater proportion of patients given placebo experienced hepatic enzyme disorders, psychiatric disorders, and insomnia. Both arms reported equal rates of hyponatremia and abdominal pain.
Chollet cited FLAME’s small patient sample and the fact that patients were selectively recruited according to degree of motor deficiency rather than consecutively enrolled as limitations of the study. He also indicated the lack of follow-up beyond 3 months as a concern.
Because fluoxetine has a hormonal target rather than a vascular one like intravenous thrombolysis with artery deocclusion, which Chollet said is the only treatment currently validated for the acute phase of stroke, the drug might produce benefits in areas such as mood, motivation, and attention. “One can accept that if attention is better and motivation is better, patients participate better in their rehabilitation program,” Chollet said. He concluded that the drug is now in the public domain, and FLAME’s positive findings suggest its use in stroke is probably in the public health interest, but that more studies are needed.
