Methodological approaches to evaluate the impact of FDA drug safety communications.

BACKGROUND: When the US FDA approves a new prescription drug there is still a great deal remaining to be learned about the safe and proper use of that product. When new information addressing these topics emerges post-approval, the FDA may issue a Drug Safety Communication (DSC) to alert patients and physicians. The effectiveness of the communication-how drug safety messaging conveyed in FDA DSCs changes patient or prescriber behavior-may depend on multiple factors, including the way physicians and patients learn about the information, their understanding of the issues conveyed, and their perception of the importance of the information. In 2013, the FDA issued two DSCs addressing critical new warnings related to products containing the sedative/hypnotic zolpidem. OBJECTIVE: In this article, we describe a core set of research initiatives that can be used to study how zolpidem-related DSCs affected subsequent physician and patient decision making. METHODS: These research initiatives include analyzing drug utilization patterns and related health outcomes; comparing zolpidem-containing products against a comparator with similar indications [eszopiclone (Lunesta)] not covered by the 2013 DSCs; and surveying patients and qualitatively evaluating the dissemination of information regarding these drugs in traditional and social-media channels. CONCLUSIONS: Using an integrated, multidisciplinary approach, we can obtain information that can be used to optimize regulatory communications by seeking to understand the impact of the information contained in FDA risk communications.

Metabolic monitoring for youths initiating use of second-generation antipsychotics, 2003-2011.

OBJECTIVE: In 2004, the American Diabetes Association (ADA) released treatment guidelines recommending metabolic screening for children and adolescents before and after initiation of second-generation antipsychotics. Prior studies showed that the guidelines coincided with a small increase in glucose testing of children and adults but had limited follow-up. This study sought to evaluate changes in metabolic screening of children initiating second-generation antipsychotics around the time of the 2004 guidelines and in the following eight years. METHODS: Study patients (N=52,407) were identified in a large nationwide commercial insurance claims database for the period January 1, 2003, through December 31, 2011. The study population was a cohort of nondiabetic new users of second-generation antipsychotics who were ages 5-18. Glucose and HbA1c tests completed before and after second-generation antipsychotic initiation were identified with Current Procedural Terminology-4 codes. Metabolic screening was also examined by second-generation antipsychotic agent prescribed and psychiatric diagnosis. RESULTS: The proportion of patients receiving a glucose test preinitiation increased from 17.9% in 2003 to 18.9% in 2004, and testing postinitiation increased from 14.7% to 16.6% in the same period. The slight increase in glucose testing was not sustained; the proportion tested dropped in the following years before rising again in 2008. Glucose screening was most common for patients taking aripiprazole. Patients with a diagnosis of hyperkinetic disorder were less likely to be tested. HbA1c testing was less frequent but had a similar usage pattern. CONCLUSIONS: The small improvement in metabolic screening immediately after the 2004 ADA guidelines were issued was not sustained. Overall, metabolic screening rates remained suboptimal throughout the study period.

Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison.

OBJECTIVE: To evaluate whether smoking status is associated with the efficacy of antiplatelet treatment in the prevention of cardiovascular events. DESIGN: Systematic review, meta-analysis, and indirect comparisons. DATA SOURCES: Medline (1966 to present) and Embase (1974 to present), with supplementary searches in databases of abstracts from major cardiology conferences, the Cumulative Index to Nursing and Allied Health (CINAHL) and the CAB Abstracts databases, and Google Scholar. STUDY SELECTION: Randomized trials of clopidogrel, prasugrel, or ticagrelor that examined clinical outcomes among subgroups of smokers and nonsmokers. DATA EXTRACTION: Two authors independently extracted all data, including information on the patient populations included in the trials, treatment types and doses, definitions of clinical outcomes and duration of follow-up, definitions of smoking subgroups and number of patients in each group, and effect estimates and 95% confidence intervals for each smoking status subgroup. RESULTS: Of nine eligible randomized trials, one investigated clopidogrel compared with aspirin, four investigated clopidogrel plus aspirin compared with aspirin alone, and one investigated double dose compared with standard dose clopidogrel; these trials include 74,489 patients, of whom 21,717 (29%) were smokers. Among smokers, patients randomized to clopidogrel experienced a 25% reduction in the primary composite clinical outcome of cardiovascular death, myocardial infarction, and stroke compared with patients in the control groups (relative risk 0.75, 95% confidence interval 0.67 to 0.83). In nonsmokers, however, clopidogrel produced just an 8% reduction in the composite outcome (0.92, 0.87 to 0.98). Two studies investigated prasugrel plus aspirin compared with clopidogrel plus aspirin, and one study investigated ticagrelor plus aspirin compared with clopidogrel plus aspirin. In smokers, the relative risk was 0.71 (0.61 to 0.82) for prasugrel compared with clopidogrel and 0.83 (0.68 to 1.00) for ticagrelor compared with clopidogrel. Corresponding relative risks were 0.92 (0.83 to 1.01) and 0.89 (0.79 to 1.00) among nonsmokers. CONCLUSIONS: In randomized clinical trials of antiplatelet drugs, the reported clinical benefit of clopidogrel in reducing cardiovascular death, myocardial infarction, and stroke was seen primarily in smokers, with little benefit in nonsmokers.

Relationship of sexual and physical abuse to pain and psychological assessment variables in chronic pelvic pain patients.

This study examines the incidence of sexual and physical abuse and its relationship to selected pain description and psychological variables in a sample of 36 chronic pelvic pain patients. Abuse was measured on a 6-item reliable scale, and abused and non-abused respondents were compared on 4 categories of variables expected to be related to the effects of abuse (pain description, functional impact of pain, other's response to pain, and psychosocial impact of pain). Results indicated that 19 of 36 patients reported prior abuse. Physical abuse was reported less commonly than sexual abuse. No differences between the abused and non-abused groups were noted on demographic, pain description, or the functional interference variables. On the psychological variables, however, the abused group reported less perceived life control, greater punishing responses to pain, and higher levels of somatization and global distress than the non-abused group. These results indicate a high incidence of sexual abuse in patients with chronic pelvic pain and suggest that abused and non-abused patients differ on psychological but not pain description or self-reported functional interference variables.

Site of pain: relationship to measures of pain description, behavior and personality.

Recent research has focused on identification of clinically meaningful subgroupings within the chronic pain population in contrast to prior emphasis on the homogeneity of these patients. The present study investigates site of pain as a potentially useful classification variable for identification of differences among chronic pain patients. In the study 92 patients presenting to a multidisciplinary pain clinic with chronic, benign pain were categorized as to site of pain (head/neck, low back, neither, both). Patients completed self-report scales assessing various activity abilities and health behaviors, a measure of pain description (McGill Pain Questionnaire (MPQ), health related measures of personality (Illness Behavior Questionnaire (IBQ) and health beliefs (Multidimensional Health Locus of Control (MHLC). One-way ANOVAs revealed significant differences as a function of pain site on a number of behavioral variables (downtime, walking, recreational and social abilities), pain description (MPQ--number of words chosen, total sum of ranks, sensory and affective) and psychological variables (IBQ--disease conviction, psychologic vs. somatic perception of illness and MHLC--internality). These results suggest site of pain to be of significance in the elaboration of behavioral and psychological response to chronic pain and implications for treatment are discussed.

Spatial distribution of pain: a descriptive characteristic of chronic pain.

Self-report of spatial distribution of pain has been employed to assess anatomic accuracy of pain description. To date, there is little information on behavioral or psychological characteristics of chronic pain patients as a function of spatial distribution of pain sites. In the present study, 92 patients presenting to a multidisciplinary pain clinic with chronic facial, back, or extremity pain enumerated total sites of pain throughout the body. Responses were categorized into low (1-2), moderate (3-5) and high (6-18) discrete sites of pain. Patients completed self-report scales assessing various activity abilities and health behaviors, a measure of pain description (McGill Pain Language Questionnaire, MPQ), and health related measures of personality (Illness Behavior Questionnaire, IBQ) and cognitive style (Multifactorial Health Locus of Control, MHLC). One-way ANOVAs revealed significant differences as a function of spatial distribution on a number of behavioral (down-time, walking, recreational, vocational and social abilities; total drug use, number of health professionals consulted), pain description (Total Words Chosen-MPQ, Sum of Ranks-MPQ, and Sensory-MPQ) and psychological variables (Disease Conviction-IBQ and Affective Disturbance-IBQ). Results suggest spatial distribution of pain site to be a useful clinical diagnostic indicator of psychological disturbance in chronic pain patients.

Stability of self-report measures of improvement in chronic pain: a five-year follow-up.

Seventy patients with chronic low-back pain not due to malignancy returned a questionnaire assessing functional status 5 years following treatment with epidural or subarachnoid nerve blocks. One hundred fifty-one patients had been surveyed 3 years earlier in an initial follow-up. The respondents to the present survey were older and more able to bend and took more medication for pain than non-respondents. The results revealed a tendency for gender-associated differences in improvement noted in the initial survey to be maintained, with women showing greater absolute improvement than men, particularly in vocational abilities. Men were somewhat more improved as a group on the current follow-up than on the initial follow-up. The use of medication for pain remained generally unchanged over time, but the number of respondents reporting the need for additional surgical treatments declined. The results were seen as indicating the need for using multiple, functional criteria in assessing response to treatment, including both global pain ratings and functional-behavioral measures of improvement.

Acupuncture and chronic pain mechanisms: the moderating effects of affect, personality, and stress on response to treatment.

The present study, part of a larger project investigating neurophysiological and psychosocial factors affecting response to acupuncture for chronic pain, compares responders and non-responders to acupuncture on a series of variables assessing personality, affect and stress. Subjects were 40 patients with pain beneath the waist level longer than 6 months duration selected from the roles of the Multidisciplinary Pain Clinic. Responders, defined as 50% or more reduction in pain estimate for greater than two weeks, were found to be less depressed, less passive and overly conventional, have shorter duration of pain, endorse less frequent exposure to stressors, and have less serious non pain-related illnesses. The findings are viewed as linking the intractability of pain states with psychosocial factors which may interfere with response to somatic modes of therapy or which may interfere via alterations of tonic neurohumoral factors. The study also in seen as supporting the importance of considering psychological variables in evaluating patients for pain treatment strategies and suggests inclusion of such variables in investigating response to other modalities of treatment for chronic pain.

Acupuncture and chronic pain mechanisms.

Forty patients with chronic pain below the waist level not amenable to conventional medical and/or surgical treatment were randomly assigned to one or two different methods of acupuncture, after studying the underlying pain mechanisms using a Multidisciplinary Pain Clinic approach and the differential spinal block (DSB). One group received acupuncture needling in the classical acupuncture points referred to as meridian loci needling (MLN) and the other group received tender area needling (TAN) with needles inserted in the dermatomal distribution of the painful areas. The responses between the two groups showed no significant difference. Results were then related to the predetermined somatopsychological basis of the individual's pain problems as classified by the DSB. A group of patinets in whom pain relief occurred upon subarachnoid injection of 0.25% procaine followed by sympathetic blockade or 0.5% procaine injection followed by hypalgesia without motor loss, also reported maximum subjective improvement in their pain level following acupuncture therapy performed at a later time. The other group of patients in whom pain persisted despite sensory and motor blockade (1% procaine) responded very poorly to acupuncture therapy. DSB was found to be complimentary to acupuncture therapy in that it facilitated patient selection for the therapy.