Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit–risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit–risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit–risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit–risk should be combined at the level of the individual patient, when possible, in addition to the benefit–risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit–risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Epidural steroid injections are used to treat lumbosacral radicular pain. However, there are no Food and Drug Administration–approved corticosteroids for lumbosacral radicular pain and all currently available injectable corticosteroids carry safety warnings about their use in epidural steroid injection procedures. SP-102 (dexamethasone injectable viscous gel) was developed to provide a safer option with extended local effect. In a randomized, double-blind, placebo-controlled, multicenter trial, 401 patients with moderate-to-severe leg pain from unilateral intervertebral lumbar disc herniation were randomized (1:1) to receive transforaminal SP-102 or sham intramuscular (IM) placebo injection and followed for 24 weeks. If clinically warranted, a repeat open-label SP-102 injection was allowed between 4 and 20 weeks for both groups. Primary and key secondary end points were change in average daily pain on the Numeric Pain Rating Scale in the affected leg and disability measured by Oswestry Disability Index over 4 weeks. Other secondary end points included time to repeat injection, pain, and quality of life assessments. Over 4 weeks, SP-102 demonstrated statistically significant pain relief compared with placebo (least-squares mean group difference −0.52 [SE 0.163] [ P = 0.002]) in the intent-to-treat population. Oswestry Disability Index mean improvement was −3.38 (1.388) (least-squares mean group difference [SE]) for SP-102 vs placebo ( P = 0.015). Median time to repeat injection was 84 days for SP-102 vs 58 days for placebo ( P = 0.001). Most other secondary end points were statistically significant for SP-102 compared with placebo. There were no serious adverse events related to study medication or procedure, no adverse events leading to death, and no AEs of special interest (paraplegia, hematoma, or infection). Trial Registration: ClinicalTrials.gov Identifier: NCT03372161.

Neuropathic pain (NP) has a population presence of up to 10%. Both systemic agents and topical agents are recommended as first-line therapy for the treatment of NP but monotherapy provides adequate pain relief only in < 50% of the cases. This has created the need for multimodal combination therapy, a practice that is becoming more common. Combination therapy with multiple systemic agents has a risk for drug–drug interactions and adverse events (AEs), while add-on therapy with a topical agent such as lidocaine patches minimizes such risks. The focus of this review was to find if there is evidence from trials that combination therapy of the topical lidocaine patches with systemic agents will have better efficacy and/or less risk of AEs than the combination of two systemic agents. Since gabapentinoids are one of the most common systemic agents used in first-line NP therapy, the objective of this review was to summarize the safety and efficacy data and evaluate the benefit–risk ratio from three gabapentinoid combinations; gabapentinoid plus opioids, gabapentinoid plus antidepressants, and gabapentinoid plus topical lidocaine patches. Reviews of clinical trials of combinations of gabapentinoids plus other systemic agents (opioids or antidepressants) were associated with increased AEs and dropouts while improvement in analgesic efficacy was inconsistent. Clinical trials where the patients were provided topical lidocaine patches when their first treatment with a gabapentinoid was inadequate demonstrated improved analgesic efficacy with minimal additional AEs. This led to the conclusion that topical lidocaine patches—associated with minimal systemic adverse effects and proven benefits in various neuropathic pain (NP) conditions—can enhance the likelihood of achieving meaningful pain relief when used as adjuvant therapy for NP.

Recently, lidocaine topical systems utilizing nonaqueous matrices have been developed and provide efficient lidocaine delivery through the skin, such that lower concentrations of drug provide equivalent or greater drug delivery than drug-in-matrix hydrogel lidocaine patches. This study characterizes drug delivery from a nonaqueous lidocaine topical system with increasing drug load both in vitro and in vivo. Topical systems formulated with either 1.8% or 5.4% lidocaine were applied to healthy volunteers’ backs (n = 15) for 12 h in a single-center, open-label, four-treatment, four-period crossover pharmacokinetic study. Subjects were dosed with either three 1.8% systems or one, two, or three 5.4% systems in each period. Blood was collected for up to 48 h, and plasma lidocaine levels were measured with a validated HPLC method. In parallel, human and mouse skin models characterized the in vitro skin permeation profile. The pharmacokinetic profile was linear between one, two, and three lidocaine 5.4% applications. Application of three lidocaine 1.8% systems (108 mg lidocaine) was bioequivalent to one lidocaine 5.4% system (108 mg lidocaine). Both topical systems remained well adhered to the skin and irritation was mild. The 5.4% system had approximately threefold higher skin permeability than the 1.8% system in the mouse and human skin models. The results indicate increasing the drug load by three times results in triple the drug delivery both in vivo and in vitro. The relationship between the in vitro permeation and in vivo absorption correlates and is nonlinear.

Topical delivery systems (TDSs) enable the direct transport of analgesics into areas of localized pain and thus minimize the side effects of administration routes that rely on systemic drug distribution. For musculoskeletal pain, clinicians frequently prescribe topical products containing lidocaine or diclofenac. This study assessed whether drug delivery from a TDS into muscle tissue occurs mainly via direct diffusion or systemic transport. An investigational TDS containing 108 mg lidocaine (SP-103, 5.4% lidocaine), a commercially available TDS containing 36 mg lidocaine (ZTlido^®, 1.8% lidocaine), and a topical pain relief gel (Pennsaid^®, 2% diclofenac) were tested. Using open flow microperfusion (OFM), interstitial fluid from the dermis, subcutaneous adipose tissue (SAT), and muscle was continuously sampled to assess drug penetration in all tissue layers. Ex vivo and in vivo experiments showed a higher diffusive transport of lidocaine compared to diclofenac. The data showed a clear contribution of diffusive transport to lidocaine concentration, with SP-103 5.4% resulting in a significantly higher lidocaine concentration in muscle tissue than commercially available ZTlido^® (p = 0.008). These results indicate that SP-103 5.4% is highly effective in delivering lidocaine into muscle tissue in areas of localized pain for the treatment of musculoskeletal pain disorders (e.g., lower back pain).

Introduction Patients receiving the standard prophylaxis dose of colchicine for gout flares are at increased risk for developing toxicity if there are pre-existing renal impairment or drug–drug interactions. Guidelines recommend exercising caution, deferring dose adjustment to the clinician’s discretion. Methods Pharmacokinetic study data for colchicine oral solution in healthy subjects was used to build a pharmacokinetic model. Using the derived pharmacokinetic disposition parameters from the best fit model and the derived parameters of clearance in patients with renal impairment, simulation of colchicine plasma levels to target 0.5–3 ng/mL with colchicine oral solution was undertaken for various dose levels in different degrees of renal impairment. Results With the standard colchicine 0.6 mg daily dose, plasma levels are expected to be therapeutic in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60–89 mL/min/1.73 m²). However, with this same 0.6 mg daily dose, patients with moderate renal impairment (eGFR 30–59 mL/min/1.73 m²) and severe renal impairment (eGFR of 15–29 mL/min/1.73 m²) would have excursions up to 10% and 36%, respectively, above the maximum tolerated level. Administering a lower dose such as 0.3 mg daily by splitting the conventional 0.6 mg tablet or by administering 0.6 mg once every-other-day (QOD) in moderate renal impairment would result in plasma colchicine levels in subtherapeutic range (< 0.5 ng/mL) for 20–70% of the dosing interval. Conclusion Analysis of pharmacokinetic model data confirms that the majority of patients with renal impairment taking colchicine solid dosage formulations will be above or below therapeutic levels, exposing them to potential side effects. However, more precise dosing with colchicine oral solution of 0.48 mg (4 mL) or 0.5 mg tablet available in certain countries for moderate renal impairment and 0.3 mg (2.5 mL) for severe renal impairment are associated with optimal levels and safer for patients with renal impairment. No dosage adjustment is needed for patients with mild renal impairment.