Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials.

INTRODUCTION: Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated. To evaluate opioids' efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for µ-opioid receptor agonists performed for US Food and Drug Administration approval. METHODS: MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, ≥10 subjects per arm, any chronic pain condition, double-blind treatment period lasting ≥12 weeks, and all µ-agonist opioids approved in the USA. RESULTS: Fifteen studies met criteria. Opioid efficacy was statistically significant (p<0.001) versus placebo for pain intensity (standardized mean difference: -0.416), ≥30% and ≥50% improvement in pain (risk difference: 0.166 and 0.137), patient global impression of change (0.163), and patient global assessment of study medication (0.194). There were minor benefits on physical function and no effect on mental function. CONCLUSION: Opioids are efficacious in the treatment of chronic non-cancer pain for up to 3 months in randomized controlled trials. This should be considered, alongside data on opioid safety, in the use of opioids for the treatment of chronic pain.

Determining the clinical importance of treatment benefits for interventions for painful orthopedic conditions.

The overarching goals of treatments for orthopedic conditions are generally to improve or restore function and alleviate pain. Results of clinical trials are generally used to determine whether a treatment is efficacious; however, a statistically significant improvement may not actually be clinically important, i.e., meaningful to the patient. To determine whether an intervention has produced clinically important benefits requires a two-step process: first, determining the magnitude of change considered clinically important for a particular measure in the relevant population and, second, applying this yardstick to a patient's data to determine whether s/he has benefited from treatment. Several metrics have been devised to quantify clinically important differences, including the minimum clinically important difference (MCID) and clinically important difference (CID). Herein, we review the methods to generate the MCID and other metrics and their use and interpretation in clinical trials and practice. We particularly highlight the many pitfalls associated with the generation and utilization of these metrics that can impair their correct use. These pitfalls include the fact that different pain measures yield different MCIDs, that efficacy in clinical trials is impacted by various factors (population characteristics, trial design), that the MCID value is impacted by the method used to calculate it (anchor, distribution), by the type of anchor chosen and by the definition (threshold) of improvement. The MCID is also dependent on the population characteristics such as disease type and severity, sex, age, etc. For appropriate use, the MCID should be applied to changes in individual subjects, not to group changes. The MCID and CID are useful tools to define general guidelines to determine whether a treatment produces clinically meaningful effects. However, the many pitfalls associated with these metrics require a detailed understanding of the methods to calculate them and their context of use. Orthopedic surgeons that will use these metrics need to carefully understand them and be aware of their pitfalls.

Instruments to Identify Prescription Medication Misuse, Abuse, and Related Events in Clinical Trials: An ACTTION Systematic Review.

UNLABELLED: Measurement of inappropriate medication use events (eg, abuse or misuse) in clinical trials is important in characterizing a medication's abuse potential. However, no gold standard assessment of inappropriate use events in clinical trials has been identified. In this systematic review, we examine the measurement properties (ie, content validity, cross-sectional reliability and construct validity, longitudinal construct validity, ability to detect change, and responder definitions) of instruments assessing inappropriate use of opioid and nonopioid prescription medications to identify any that meet U.S. and European regulatory agencies' rigorous standards for outcome measures in clinical trials. Sixteen published instruments were identified, most of which were not designed for the selected concept of interest and context of use. For this reason, many instruments were found to lack adequate content validity (or documentation of content validity) to evaluate current inappropriate medication use events; for example, evaluating inappropriate use across the life span rather than current use, including items that did not directly assess inappropriate use (eg, questions about anger), or failing to capture information pertinent to inappropriate use events (eg, intention and route of administration). In addition, the psychometric data across all instruments were generally limited in scope. A further limitation is the heterogeneous, nonstandardized use of inappropriate medication use terminology. These observations suggest that available instruments are not well suited for assessing current inappropriate medication use within the specific context of clinical trials. Further effort is needed to develop reliable and valid instruments to measure current inappropriate medication use events in clinical trials. PERSPECTIVE: This systematic review evaluates the measurement properties of inappropriate medication use (eg, abuse or misuse) instruments to determine whether any meet regulatory standards for clinical trial outcome measures to assess abuse potential.

Review of the performance of quantitative sensory testing methods to detect hyperalgesia in chronic pain patients on long-term opioids.

BACKGROUND: Opioid-induced hyperalgesia is a clinical syndrome whereby patients on long-term opioids become more sensitive to pain while taking opioids. Opioid-induced hyperalgesia is characterized by increased pain intensity over time, spreading of pain to other locations, and increased pain sensation to external stimuli. To characterize opioid-induced hyperalgesia, laboratory methods to measure hyperalgesia have been developed. To determine the performance of these methods, the authors conducted a systematic review of clinical studies that incorporate measures of hyperalgesia in chronic pain patients on long-term opioids. METHODS: PubMed and Cochrane databases were searched (terms: opioid induced hyperalgesia, study or trial, and long-term or chronic). Studies published in English were selected if they were conducted in chronic pain patients on long-term opioids and incorporated measures of hyperalgesia; acute/single-dose studies and/or conducted in healthy volunteers were excluded. RESULTS: Fourteen articles made the final selection (11 were selected from the search and 3 others were found from additional sources); there was one randomized controlled trial, one prospective controlled study, three prospective uncontrolled studies, and nine cross-sectional observation studies. Hyperalgesia measurement paradigms used included cold pain, heat pain, pressure pain, electrical pain, ischemic pain, and injection pain. Although none of the stimuli were capable of detecting patients' hyperalgesia, heat pain sensitivity showed some promising results. CONCLUSIONS: None of the measures reviewed herein met the criteria of a definitive standard for the measurement of hyperalgesia. Additional studies that use improved study design should be conducted.

A review of the use of the number needed to treat to evaluate the efficacy of analgesics.

UNLABELLED: Standardized measures of efficacy are needed to compare analgesic efficacy across trials. The number needed to treat (NNT) is considered a statistically robust and readily interpretable measure to rank the efficacy of treatments, including analgesics. The NNT has become widely utilized to compare the efficacy of chronic pain treatments, helping physicians make treatment decisions and informing decisions for market access, reimbursement, and treatment guidelines. However, the NNT is associated with specific weaknesses in calculation and interpretation not associated with other methods for integrating trial data. These weaknesses include distortions in calculation as placebo effects approach treatment effects, with the possibility of infinite values; difficulties in estimating the NNT's confidence interval; and difficulties in interpretation. The NNT also requires selecting cutoffs of the original variable for dichotomization, with the NNT often changing depending on the cutoff. The NNT also suffers from problems common to other placebo-adjusted endpoints, including being sensitive to study-related and external factors (eg, year of publication). Therefore, clinicians and other stakeholders need to be aware of these issues to correctly calculate, use, and interpret the NNT. Nevertheless, efficacy, as measured by any variable, is only one aspect of a treatment to be considered in determining its place in therapy. PERSPECTIVE: The NNT has become widely utilized to compare the efficacy of chronic pain treatments. This article reviews the uses of the NNT and the potential problems associated with its calculation, use, and interpretation. Clinicians should be aware of these issues when interpreting clinical trial data based on the NNT.

Assessment of pain and activity using an electronic pain diary and actigraphy device in a randomized, placebo-controlled crossover trial of celecoxib in osteoarthritis of the knee.

OBJECTIVE: The primary goal was to determine whether a composite measure of pain and activity is a more responsive assessment of analgesic effect than pain alone or activity alone in patients with osteoarthritis (OA) of the knee. DESIGN: We conducted a randomized, double-blind, placebo-controlled, 2-period, crossover study of celecoxib vs. placebo in subjects with chronic pain due to knee OA. Patients with knee OA and baseline pain intensity score ≥4 on a 0-10 numerical rating scale (NRS) before each period were randomized. Pain endpoints included in-clinic pain score (24-hour and 1-week recall), daily paper diary pain score, current pain on an electronic pain diary (each on NRS), and WOMAC pain subscale. Activity measures included WOMAC function subscale and actigraphy using a device. Three composite pain-activity measures were prespecified. RESULTS: Sixty-three patients were randomized and 47 completed the study. The WOMAC pain subscale was the most responsive of all five pain measures. Pain-activity composites resulted in a statistically significant difference between celecoxib and placebo but were not more responsive than pain measures alone. However, a composite responder defined as having 20% improvement in pain or 10% improvement in activity yielded much larger differences between celecoxib and placebo than with pain scores alone. Actigraphy was more responsive than the WOMAC function scale, possibly due to lower placebo responsiveness. CONCLUSION: We have identified composite pain-activity measures that are similarly or more responsive than pain-alone measures in patients with OA. Further research is warranted to determine the optimal method for computing these composites.

Predictors of Response in Patients With Postherpetic Neuralgia and HIV-Associated Neuropathy Treated With the 8% Capsaicin Patch (Qutenza).

OBJECTIVES: Qutenza is a high-dose capsaicin patch used to relieve neuropathic pain from postherpetic neuralgia (PHN) and HIV-associated neuropathy (HIV-AN). In clinical studies, some patients had a dramatic response to the capsaicin patch. Our objective was to determine the baseline characteristics of patients who best benefit from capsaicin patch treatment. METHODS: We conducted a meta-analysis of 6 completed randomized and controlled Qutenza studies by pooling individual patient data. Sustained response was defined as>50% decrease in the mean pain intensity from baseline to weeks 2 to 12, and Complete Response as an average pain intensity score≤1 during weeks 2 to 12. Logistic regression was used to identify predictors of response and Complete Response, and subgroups of patients who respond best to the capsaicin patch. RESULTS: Baseline pain intensity score (BPIS)≤4 was a predictor of Sustained and Complete Response in PHN and HIV-AN patients; absence of allodynia and presence of hypoesthesia, and a McGill Pain Questionnaire (MPQ) sensory score <22 were predictors of Sustained Response in PHN patients; female sex was a predictor of Sustained and Complete Response in HIV-AN patients. Thus, characteristics associated with the highest chance of responding to the capsaicin patch were, for PHN, BPIS≤4, MPQ sensory score≤22, absence of allodynia, and presence of hypoesthesia; for HIV-AN, they were female sex and BPIS≤4. Patients with these characteristics had a statistically significantly greater chance of responding to the capsaicin patch than other patients. DISCUSSION: We identified subpopulations of PHN and HIV-AN patients likely to benefit from the capsaicin patch.

Qutenza (capsaicin) 8% patch onset and duration of response and effects of multiple treatments in neuropathic pain patients.

INTRODUCTION: Qutenza (capsaicin) 8% patch is used to treat various neuropathic indications, including postherpetic neuralgia (PHN) and human immunodeficiency virus-associated neuropathy (HIV-AN). OBJECTIVES: We conducted a meta-analysis of Qutenza studies to describe clinical phenomena of effects of Qutenza treatment better, such as onset and duration of pain relief, and the need for retreatments. METHODS: The meta-analyses combined individual patient data (1313 participants with PHN and 801 with HIV-AN) from 7 completed randomized, double-blind, controlled studies. Studies had similar designs, and all used the Qutenza patch (8% capsaicin) and a low-dose control patch (0.04% capsaicin). A 30% response was defined as a ≥30% decrease in mean pain intensity score during week 2 to end of follow-up; complete pain relief was defined as an average pain intensity ≤1 during week 2 to end of follow-up. Duration of response was calculated using the data from long-term studies as the time from onset of response to offset of response, retreatment, or end of follow-up (whichever occurred first). RESULTS: Overall 44% of PHN and 41% of HIV-AN patients had a 30% response, and 11% and 7%, respectively, had complete pain relief 2 to 12 weeks after treatment with Qutenza. The mean (median) onset of response to Qutenza was 3.4 (1) days for PHN and 6.5 (4) days for HIV-AN (delayed due to an initial increase in discomfort). The mean (median) duration of response after 1 Qutenza treatment was 5 (3) months. Of the patients followed-up for 12 months, 40% PHN and 36% HIV-AN patients had a 30% response, and 9% and 10%, respectively, had complete pain relief from week 2 to end of follow-up. CONCLUSIONS: Qutenza is effective in a high proportion of patients. In patients who respond to Qutenza, analgesia starts within a few days of treatment and lasts on average 5 months.

Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations.

As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential.

Efficacy of Qutenza® (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database.

Qutenza® is a capsaicin patch used to treat peripheral neuropathic pain, including postherpetic neuralgia (PHN) and human immunodeficiency virus-associated neuropathy (HIV-AN). The Qutenza Clinical Trials Database has been assembled to more fully characterize the effects of Qutenza. We conducted a within-subject meta-analysis of Qutenza studies to further define the medication's efficacy profile across studies. The meta-analysis combined individual patient data from randomized, controlled studies of Qutenza in peripheral neuropathic pain (1458 subjects treated with approved doses of Qutenza or control patches; 1120 with PHN and 338 with HIV-AN). These 7 studies had similar designs and were performed with the high-dose 8% capsaicin Qutenza patch and a 0.04% low-dose control patch. The difference between treatment groups for the primary efficacy end point of percentage change from baseline to weeks 2 to 12 on pain intensity score was calculated. Response was defined as a ≥ 30% decrease in mean pain intensity score during weeks 2 to 12. The overall between-group difference in percentage change from baseline in pain intensity was 8.0% (95% confidence interval 4.6, 11.5; P<.001), which statistically significantly favored Qutenza over low-dose control. Qutenza superiority was demonstrated for both PHN and HIV-AN patients for the primary end point and the end point proportion of 30% pain reduction response, and for PHN patients for the end point of proportion of 50% pain reduction response. These results confirm that Qutenza is effective for the treatment of both PHN and HIV-AN compared to low-dose control patch.

Tampering with prescription opioids: nature and extent of the problem, health consequences, and solutions.

BACKGROUND: Transdermal and solid oral prescription opioid (PO) formulations can be abused by ingesting (with or without tampering), snorting, or injection (both requiring tampering). OBJECTIVE: To determine the patterns of tampering with POs for abuse. METHODS: Information was collected from published studies and databases. RESULTS: Tampering with POs for abuse is common practice. Ingestion is the most prevalent method of abuse, followed by snorting and injection. From 1992 to 2002, injecting POs has decreased in favor of ingesting and snorting. Methods of abuse vary widely by product. Abuse methods with the highest morbidity are injection and inhalation. CONCLUSIONS: The seriousness of health outcomes associated with tampering with POs warrants the development of PO formulations that prevent or deter tampering.

Usefulness of prescription monitoring programs for surveillance--analysis of Schedule II opioid prescription data in Massachusetts, 1996-2006.

PURPOSE: Electronic prescription monitoring programs (PMPs) have been developed in many states as a public health surveillance tool. We analyze herein 11 years of Massachusetts PMP data to evaluate trends in opioid prescribing, dispensing, and usage. METHODS: Prescription records from the Massachusetts PMP for Schedule II opioids from fiscal year 1996 to 2006 were analyzed. 'Questionable activity' (potential 'doctor shopping') estimates were based on individual use of multiple prescribers and pharmacies, and early refills. RESULTS: The number of prescriptions, doses prescribed, and individuals receiving Schedule II prescription opioids steadily increased from 1996 to 2006. Most individuals (87.5%) used 1-2 prescribers, 1-2 pharmacies, and had no early refills (2006). The greater the number of prescribers used, the greater the number of pharmacies used. When defined as the use of >or=4 prescribers and >or=4 pharmacies, questionable activity accounted for 2748 individuals, 47 953 prescriptions, and 2 966 056 doses (2006). The Schedule II opioid most highly associated with questionable activity was short-acting oxycodone. CONCLUSIONS: PMPs can become a useful public health surveillance tool to monitor the medical and non-medical use of prescription opioids and to inform public health and safety policy.

Direct nucleic acid diagnostic tests for bacterial infectious diseases: streptococcal pharyngitis, pulmonary tuberculosis, vaginitis, chlamydial and gonococcal infections.

Partnering with a reference lab can actually help grow a referring lab's own business. The reference lab provides a hospital's physicians with access to unique tests and clinical information and broadens the scope and depth of the referring lab's menu. As medicine moves toward prescribed treatments based on a patient's individual genotype or phenotype, the reference lab will play an even bigger role in helping the hospital to educate physicians and their patients to the most efficient testing strategies consistent with good patient management.