Arnold R. Gammaitoni

Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: A review of the literature

The safety, tolerability, and efficacy of the lidocaine patch 5% (Lidoderm®), a targeted peripheral analgesic with an FDA‐approved indication for the treatment of postherpetic neuralgia, has been well established. Recent case reports and studies have suggested potential efficacy in other neuropathic and nonneuropathic pain conditions. Several pharmacokinetic studies have demonstrated minimal systemic absorption with 12‐, 18‐, and 24‐hour/day dosing. Mean maximum plasma concentrations have shown the lidocaine patch to possess a minimal risk for systemic toxicities or drug‐drug interactions. The most common adverse events generally involve mild skin reactions. There have been no drug‐drug interactions noted in clinical trials. Recent evidence suggests that extended application does not result in A‐β‐mediated sensory loss at the application site, which is particularly important in patients who already have a degree of sensory loss due to their underlying condition. The lidocaine patch provides a treatment option that carries a relatively low systemic adverse event and drug‐drug interaction risk burden, even with continuous application of up to four patches per day.

Clinical application of opioid equianalgesic data

Physicians and other healthcare professionals may often be faced with the need to change opioids during the course of a patients opioid analgesic care due to a number of clinical reasons. The act of converting opioid analgesics, for many physicians, nurses, and pharmacists, who do not receive adequate training, remains a challenging and often uncomfortable aspect of pain treatment. Part of the challenge clinicians face is secondary to the relatively weak literature evidence base that exists to support the equianalgesic ratios provided in textbooks, journals, and other medical resources. Another aspect involves the lack of a widely recognized treatment algorithm or guideline to assist clinicians with opioid conversion. The final decision on which opioid dose to prescribe must involve a thorough clinical assessment to minimize the risk of prescribing inappropriate opioid doses over or under the patients actual need. The purpose of this paper is to provide the clinician with an approach for dealing with the conversion between opioid analgesics that is standardized, yet allows for individualized results to meet unique patient needs. We present a 5-step process as a guide for clinicians faced with the need to change a patients opioid regimen. This approach may help to build a comfort level when dealing with the clinical challenges of converting from one opioid to another.

Pharmacokinetics and Tolerability of Lidocaine Patch 5% with Extended Dosing

OBJECTIVE: To assess the pharmacokinetics, safety, and tolerability of lidocaine delivered via 4 lidocaine 5% patches applied for 18 h/d for 3 consecutive days in healthy volunteers. METHODS: A prospective, nonrandomized, open-label trial was conducted to determine the pharmacokinetics of 4 lidocaine patches 5% applied to the backs of 20 volunteers on days 1, 2, and 3. On each day, serum samples were collected prior to, during, and after patch application. Safety and tolerability assessments included skin evaluations, monitoring of clinical adverse events and vital signs, 12-lead electrocardiograms, and laboratory testing. RESULTS: For days 1, 2, and 3, the mean ± SD maximum concentrations were 145.1 ± 42.4, 153.0 ± 40.7, and 153.8 ± 51.4 ng/mL, respectively; the median × to peak plasma concentration were 18.0, 16.5, and 16.5 hours, respectively; the mean ± SD trough concentrations were 83.0 ± 29.0, 85.7 ± 31.1, and 77.0 ± 26.9 ng/mL, respectively; and the mean ± SD AUCs over 24 hours were 2089.2 ± 632.5, 2659.2 ± 726.8, and 2675.7 ± 819.2 ng ± h/mL, respectively. The patch was well tolerated; local skin reactions were generally minimal and self-limited. CONCLUSIONS: The application of 4 lidocaine patches 5% for 18 h/d for 3 consecutive days is well tolerated; steady-state plasma concentrations are achieved within 3 days. Maximum plasma concentrations of lidocaine are similar to those reported in a previous study with 3 lidocaine patches 5% applied for 12 h/d for 3 consecutive days.

Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the Neuropathic Pain Scale.

SUMMARY Objective: To determine the impact of the lidocaine patch 5% on pain qualities associated with chronic pain from post-herpetic neuralgia (PHN), painful diabetic neuropathy (DN), and low-back pain (LBP), using the Neuropathic Pain Scale (NPS). Patients and methods: Patients with PHN, painful DN, and LBP were enrolled if they had partial response to gabapentin-containing analgesic regimens and if they reported moderate-to-severe pain on the NPS at study enrollment. Eligible patients were included in an open-label, non-randomized, prospective, 2-week study across 7 clinical trial sites in the United States. The lidocaine patch 5% was applied to the area of maximal pain, using no more than a total of 4 patches changed every 24 h. Patients were maintained on their other analgesic regimens with no dose adjustment or additions allowed. Treatment effect was measured by change from baseline to Week 2 in 4 composite measures of the NPS: NPS-10, NPS-4, NPS-8, and NPS-non-allodynia. Safety was assessed by adverse events (AEs), dermal assessment of application site(s), and skin sensory testing. Results: In the combined patient population (n = 77), 2 weeks of treatment with the lidocaine patch 5% significantly improved all 4 composite measures ( p < 0.01). In the subgroup analyses, the lidocaine patch 5% demonstrated numerical advantage for all 4 NPS composite measures for the PHN patients (n = 8), and significantly improved all 4 composite measures for the painful DN patients (n = 41; p < 0.001) and LBP patients (n = 28; p ≤ 0.005). Overall, 8 patients (10%) experienced mild-to-moderate treatment-related AEs. Conclusions: The lidocaine patch 5% effectively reduces the intensity of all common pain qualities in patients with moderate-to-severe chronic pain resulting from PHN, painful DN, or LBP. Treatment is well tolerated in combination with other analgesic regimens, with no reports of serious AEs or adverse drug interactions. Assessment scales such as the NPS may offer the possibility to differentiate between various pain states and to assess treatment outcomes for various pain qualities associated with a given pain state.

Numbers-needed-to-treat analyses – Do timing, dropouts, and outcome matter? Pooled analysis of two randomized, placebo-controlled chronic low back pain trials

&NA; Numbers‐needed‐to‐treat (NNT) are useful for presenting treatment response, conveying the clinical relevance of results. NNTs are typically calculated at a landmark endpoint (end of trial), but often using the last observation carried forward (LOCF), which ignores patient discontinuations. We compared NNTs in chronic low back pain (CLBP) using three separate imputation methods, using data from two identical 12‐week trials comparing etoricoxib 60 mg (N = 210), 90 mg (N = 212), and placebo (N = 217). We calculated the number of patients with improvements in pain intensity from baseline of ≥15%, ≥30%, ≥50%, and ≥70% at 2, 4, 8, and 12 weeks of treatment. For longitudinal response over time, patient discontinuations were assigned a 0% improvement from dropout forward. Landmark response at week 12 was assessed using LOCF and completer approaches, using only observed (non‐missing) data. The longitudinal approach was most conservative; after 12 weeks 65% of patients taking etoricoxib had ≥15% improvement, 60% had ≥30% improvement, 45% had ≥50%, improvement, and 30% had ≥70% improvement, with placebo rates approximately 55%, 45%, 30%, and 15%, respectively. Response rates were higher with landmark analyses. Landmark NNTs at week 12 were generally similar or slightly lower (better) than those from a longitudinal approach, but results were inconsistent. Landmark analyses provide no information on response variability, as is obtained with longitudinal analysis. Outcome, imputation method, and reporting method are intimately connected and need to be considered alongside trial quality and validity to make sensible comparisons between treatments.

Lidocaine patch 5% and its positive impact on pain qualities in osteoarthritis: results of a pilot 2-week, open-label study using the Neuropathic Pain Scale

SUMMARY Objective: To determine the impact of the lidocaine patch 5% on distinct pain qualities associated with osteoarthritis (OA) through use of the Neuropathic Pain Scale (NPS), an assessment tool designed to assess intensity of various pain qualities (i.e. sharp, dull). Patients and methods: Patients were enrolled in a prospective, open-label, non-randomized, parallel-group, 2-week study involving 8 clinical trial sites in the United States. Eligible patients had radiographic evidence of OA involving one or both knees and reported moderate-to-severe pain (despite prn or stable doses of analgesics) on the NPS at study enrollment. Patients on prn analgesics were discontinued from all analgesic regimens prior to study entry and received lidocaine patch 5% as monotherapy. Those on stable doses of analgesics were continued on their other analgesic regimens with no additions or dose alterations allowed other than the lidocaine patch 5% as add-on therapy. The lidocaine patch 5% was applied to the area of maximal pain, using no more than a total of 4 patches changed every 24 h. Effectiveness was measured by change from baseline to Week 2 in 4 composite measures of the NPS: NPS-10, NPS-4, NPS-8, and NPS-non-allodynia. Safety was assessed by adverse events (AEs), dermal assessment of application site(s), and skin sensory testing. Results: In the combined patient population (n = 100), 2 weeks of treatment with lidocaine patch 5% significantly improved all 4 NPS composite measures ( p < 0.001). Separate analyses by subgroups revealed significant improvements in all 4 composite measures for both the monotherapy group (n = 12; p < 0.01) and add-on therapy group (n = 88; p < 0.001). No treatment-related AEs were reported for the monotherapy group. In the add-on therapy group, 5 patients experienced mild-to-moderate treatment-related AEs. Conclusions: In patients with moderate-to-severe OA of the knee, 2 weeks of treatment with the lidocaine patch 5% significantly reduces the intensity of pain qualities as measured by all 4 NPS composite measures. Our results coincide with previously reported improvements in pain and physical function in the same patient population, as measured by the Western Ontario and McMaster Universities OA Index. Measuring the various qualities of pain appears to be a valid approach for assessing clinical outcomes in the treatment of OA pain. Pain measures such as the NPS can capture the multi-dimensional properties of a patients pain experience and may offer clinicians the possibility to identify differential effects of analgesic treatments on various pain qualities associated with OA.

The dimensions of pain quality: factor analysis of the Pain Quality Assessment Scale.

ObjectiveTo provide a better empirical understanding of the dimensionality of neuropathic and non-neuropathic pain quality. MethodAn exploratory factor analysis (FA) was performed with baseline pain quality data [assessed using the Pain Quality Assessment Scale (PQAS)] from patients with osteoarthritis of the knee (n=368) and low back pain (n=455) who had participated in a series of analgesic clinical trials. The results of the FA were then confirmed in a sample of patients with neuropathic pain secondary to carpal tunnel syndrome (n=138). Comparisons between the diagnostic groups on scale scores derived from the FA results were also made using t tests. ResultsThree clear pain quality factors emerged that seemed to represent (1) paroxysmal pain sensations (PQAS descriptors: shooting, sharp, electric, hot, and radiating), (2) superficial pain (itchy, cold, numb, sensitive, and tingling), and (3) deep pain (aching, heavy, dull, cramping, and throbbing). The PQAS tender pain item did not load strongly on any of the 3 factors. DiscussionThe findings support the hypothesis that pain qualities cluster into distinct groups. If replicated in additional samples, the pain quality domains identified may provide clinicians and researchers with a useful way to summarize data from pain quality measures, and may also provide meaningful end points that would allow for treatment differentiation between various pharmacologic entities.

Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways

Two 14‐day, randomized, open‐label, parallel‐group studies examined the effects of extended‐release (ER) oxymorphone on CYP2C9 or CYP3A4 metabolic activities in healthy subjects. On days −1, 7, and 14, subjects received either a CYP2C9 probe (tolbutamide 500 mg) or CYP3A4 probes (midazolam and [14C N‐methyl]‐erythromycin for the erythromycin breath test). Subjects were randomized to 5 groups: high‐dose oxymorphone ER (3 × 20 mg q12h) + naltrexone (50 mg q24h); low‐dose oxymorphone ER (10–20 mg q12h); rifampin (2 × 300 mg q24h), an inducer of CYP2C9 and CYP3A4 activities; naltrexone (50 mg q24h); or CYP probes alone (controls). Probe metabolism was significantly altered by rifampin on days 7 and 14 (P < .05), whereas probe metabolism was not significantly affected by low‐dose oxymorphone ER or by high‐dose oxymorphone ER plus naltrexone. Oxymorphone ER exhibits a minimal potential for causing metabolic drug‐drug interactions mediated by CYP2C9 or CYP3A4.

Use of the lidocaine patch 5% in reducing intensity of various pain qualities reported by patients with low-back pain.

SUMMARY Objective: To determine the impact of the lidocaine patch 5% on pain qualities associated with low-back pain (LBP) through use of the Neuropathic Pain Scale (NPS). Patients and methods: Patients were enrolled in an open-label, non-randomized, prospective, 6-week study involving 8 clinical trial sites in the United States. Eligible patients had non-radicular LBP and reported moderate-to-severe pain on the NPS at study enrollment. Patients were stratified to 3 groups based on the duration of their LBP, defined as acute/sub-acute (< 3 months), short-term chronic (3–12 months), or long-term chronic LBP (> 12 months). The lidocaine patch 5% was applied to the area of maximal pain, using no more than a total of 4 patches changed every 24 h. Effectiveness was measured by change from baseline to Week 2 and Week 6 in 4 composite measures of the NPS: NPS-10, NPS-4, NPS-8, and NPS-non-allodynia. Safety was assessed by adverse events (AEs), dermal assessment of application site(s), and skin sensory testing. Results: In the combined patient population (n = 71), 6 weeks of treatment with lidocaine patch 5% significantly improved all 4 NPS composite measures at both Week 2 and Week 6 ( p < 0.001). Separate analyses by subgroups revealed differential improvements in the 4 composite measures. Eleven patients (15.5%) experienced treatment-related AEs that were primarily mild-to-moderate and dermal in nature. Conclusions: In patients with moderate-to-severe LBP, 2 weeks and 6 weeks of treatment with the lidocaine patch 5% significantly reduces the intensity of pain qualities as measured by all 4 NPS composite measures. Lidocaine patch 5% is well tolerated with few systemic AEs and may provide beneficial pain relief for patients receiving multidisciplinary treatment without increasing risks for adverse drug interactions. Pain scales such as the NPS offer the ability to measure various pain qualities experienced by LBP patients and may allow clinicians to assess the treatment impact of different medications.

Topical lidocaine patch 5% may target a novel underlying pain mechanism in osteoarthritis.

SUMMARY Recent literature and animal research has provided insight to potentially new analgesic targets for managing osteoarthritis (OA) pain. Primary afferent neurons located in affected joints express excessive amounts of abnormally functioning sodium (Na) channels on their surface in response to the inflammatory process. These Na channels may play an integral role in production of pain and hyperalgesia. Hence, the authors set out to conduct a 2-week, open-label, multicenter proof-of-concept study to evaluate the effectiveness and safety of lidocaine patch 5% monotherapy in adults with OA pain of the knee ( n = 20). Patients with OA of one or both knees who were experiencing inadequate pain relief (defined as an average daily pain intensity of > 4 on a 0 to 10 pain scale) with their current analgesic regimen (i.e. APAP, NSAIDs, COX-2 inhibitors, tramadol) were enrolled and had all analgesic medications discontinued. Treatment with the lidocaine patch 5% resulted in significant improvements in the Western Ontario and McMaster Universities OA Index (WOMAC) pain, stiffness, physical function subscales and composite index (48.4, 41.1, 47.0, and 46.8% improvements respectively, p < 0.01). In addition, significant improvement was noted for pain intensity, pain relief, and pain interference with quality of life as measured by the Brief Pain Inventory ( p < 0.05). The lidocaine patch 5% was generally well tolerated and no patients discontinued due to treatment-related adverse events. Given the open-label design, lack of a control group, and small sample size, the findings from our pilot study need to be confirmed by larger randomized controlled trials. Topical lidocaine patch 5% may provide clinicians with a novel, non-systemic therapy for OA pain with a unique mechanism of action.