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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.

Supplemental Digital Content is Available in the Text., Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Objective: To explore behaviors related to prescription opioid abuse and diversion in individuals who self-reported past recreational (nonmedical) opioid use. Design: A questionnaire was developed and included in two abuse potential clinical studies conducted in Canada (Toronto, ON, August 2010 to January, 2011) and the United States (Salt Lake City, UT, February-May 2011). Participants: Recreational opioid users. Main outcome measure(s): Self-reported behaviors related to prescription opioid abuse and diversion. Results: The questionnaire was completed by 174 participants in the Canadian study and 80 participants in the US study. Most participants reported that they used prescription opioids for nonmedical purposes a few times a month. Most had taken their first prescription opioid between the ages of 12 and 24 years and the two most common reasons were to treat pain or to feel high/stoned. When asked about specific opioids taken for nonmedical purposes in the past year, oxycodone, acetaminophen with codeine, and morphine were commonly used by both cohorts, whereas hydrocodone use was substantially greater in the US cohort versus the Canadian cohort. Participants reported various tampering methods and routes of administration, with swallowed whole, crushed and snorted, and chewed/crushed and swallowed as the most prevalent. Most participants indicated taking other drugs with prescription opioids to get high, most commonly marijuana and alcohol. The most common sources for obtaining prescription opioids were family/friends. Conclusions: Two cohorts of recreational opioid users from Canada and the United States reported similar experiences with various prescription opioids and indicated a predominance of diversion from family/friends.

Beatrice Setnik,1 Carl L Roland,1 Kenneth W Sommerville,1,2 Glenn C Pixton,1 Robert Berke,3,4 Anne Calkins,5 Veeraindar Goli1,2 1Pfizer Inc, 2Duke University Medical Center, Durham, NC, 3Family Health Medical Services PLLC, Mayville, NY, 4Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY, 5New York Spine & Wellness Center, Syracuse, NY, USA Objective: To compare the investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion with patient self-reports of these activities in a population with chronic pain. Methods: As a secondary objective of an open-label, multicenter, primary care-based clinical study to evaluate the success of converting opioid-experienced patients with chronic pain to morphine sulfate with sequestered naltrexone hydrochloride, risk for misuse, abuse, and diversion was assessed using two nonvalidated questionnaires: one was completed by the investigator and another by the patient (Self-Reported Misuse, Abuse, and Diversion [SR-MAD]). In addition, the validated Current Opioid Misuse Measure (COMM) test and urine drug test were used. Results: Of the 684 patients assessed by the investigators, 537 returned the self-assessment, SR-MAD. Most patients were assigned by the investigator as low risk for misuse (84.2%), abuse (89.3%), and diversion (94.3%). Of the patients who returned SR-MAD, 60% indicated having taken more opioids than prescribed and 10.9% reported chewing or crushing their opioids in the past. Of the patients who completed COMM, 40.6% were deemed as having aberrant behaviors. COMM results correlated with the risk levels from the investigator assessment. One-third of patients (33.8%) had at least one abnormal urine drug test result. Conclusion: More research is needed to better understand the gap between the investigator assessment of potential risk for misuse, abuse, and diversion and the actual extent of these behaviors among patients with chronic pain. Keywords: opioid, abuse, misuse, diversion, chronic pain

Objective: To evaluate the long-term safety of oxycodone-hydrochloride and sequestered naltrexone-hydrochloride (ALO-02) administered for up to 12 months. Design: Open-label, single-arm safety study. Setting: Thirty-two US research centers (ClinicalTrials.gov identifier NCT01428583). Patients: Three hundred ninety-five adults (opioid experienced and opioid naive) with moderate-to-severe chronic noncancer pain (CNCP). Interventions: Open-label, oral ALO-02 capsules, daily dose ranging from 20 to 160 mg oxycodone for up to 12 months. Main outcome measures: Number and type of adverse events (AEs) and drug-related AEs, including assessments of withdrawal (Clinical Opiate Withdrawal Scale; COWS), pharmacokinetics, efficacy, and aberrant behaviors (Current Opioid Misuse Measure). Results: A total of 193 (48.9 percent) patients received ALO-02 for ≥ 181 days and 105 (26.6 percent) patients for ≥ 361 days. The most common treatment-emergent AEs were nausea (25.3 percent), constipation (21.3 percent), vomiting (13.9 percent), and headache (11.6 percent). The most common drug-related AEs were constipation (18.0 percent), nausea (14.9 percent), somnolence (8.4 percent), fatigue (6.8 percent), dizziness (5.6 percent), and vomiting (5.1 percent). A majority of patients (86.6 percent) had a maximum COWS total score below the level for mild withdrawal symptoms at every visit throughout the study. Pain severity scores as measured by the short Form of the Brief Pain Inventory (BPI-SF) decreased over time. Conclusions: Repeat dosing of ALO-02 for up to 12 months is safe and well tolerated in a CNCP population of both opioid-experienced and opioid-naive patients. ALO-02 demonstrated a safety profile consistent with extended-release opioids and the expected analgesic efficacy. The addition of sequestered naltrexone had no significant clinical effect on patients when taken as directed.

Objectives To compare the pharmacodynamic effects, including self-reports of “drug liking” and “high,” of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules (MSN), crushed morphine sulfate controlled-release (CR) tablets, and placebo in an abuse potential study. Design Randomized, double-blind, placebo-controlled, three-way crossover study. Setting Single-center. Subjects Nondependent recreational opioid users. Interventions Orally administered crushed MSN (120-mg morphine sulfate and 4.8-mg naltrexone hydrochloride), crushed 120-mg morphine sulfate CR, and placebo. Outcome Measures Subjective ratings (100-point visual analog scales) of positive drug effects (drug liking, high, good effects, take drug again, and overall drug liking), any effects, and negative effects (bad effects, feel sick, nausea, sleepy, and dizzy), along with pupillometry, pharmacokinetic (PK), and safety assessments. Results Crushed morphine sulfate CR significantly increased ratings of all positive subjective measures relative to placebo (P

Objective: To evaluate whether intact or crushed doses of an extended-release formulation of morphine sulfate surrounding an inner core of sequestered naltrexone (MSN) induces signs and symptoms of withdrawal in opioid-dependent patients. Design: Randomized, double-blind, two-way crossover study. Setting: Single center. Patients: Fourteen patients with chronic moderate-to-severe noncancer pain receiving opioids were enrolled into the study; six completed the maintenance and treatment phases prior to early study discontinuation for issues with manufacturing; eight discontinued: adverse effects (4), noncompliance (1), patient decision (1), study termination (2). Interventions: Patients were titrated to a stable dose of MSN (ranging from 30/1.2 to 100/4.0 mg of morphine/naltrexone) that was used in the single-dose crossover evaluation of crushed and intact MSN. Main outcome measures: Clinical Opiate Withdrawal Scale (COWS). Results: Clinically significant withdrawal (COWS ≥ 13) was observed with rapid onset (≥ 0.8 hours postdose) in three patients (50 percent) following treatment with crushed MSN at the highest doses administered of ≥ 60/2.4 mg. Although naltrexone exposure was negligible following exposure to intact MSN, increasing plasma levels of naltrexone and 6-β-naltrexol were associated with COWS score ≥ 13 in patients who received crushed MSN. COWS ≥ 13 was observed in one patient receiving intact MSN without quantifiable naltrexone concentrations. Conclusion: Crushing the MSN capsule may precipitate moderate-to-severe signs and symptoms of opioid withdrawal in opioid-dependent individuals. The negligible exposure to naltrexone following exposure to intact MSN supports that intact capsules may be taken safely without precipitating withdrawal in opioid-dependent individuals.

OBJECTIVE: To evaluate the pharmacodynamic (PD) effects of morphine sulfate and naltrexone hydrochloride extended-release (MSN) capsules compared with controlled-release morphine sulfate (MS) and placebo when crushed and administered intranasally.METHODS: The present study was a randomized, double-blinded, placebo-controlled, single-dose (30 mg), three-way crossover study in healthy, nondependent recreational opioid users. PD measures included assessment of subjective drug effects using visual analogue scales (VAS) ranging from 0 to 100 and assessments of pupil diameter. Blood samples were collected for pharmacokinetic analyses.RESULTS: Both MS and MSN showed significantly higher PD values compared with placebo. MSN showed significantly lower scores for drug liking and high VAS scores on both mean peak effect (Emax) (69.6 and 55.2, respectively) and in area under the effect curve over 2 h (86.3 and 66.7, respectively) following dosing compared with MS (Emax87.6 and 86.6, respectively; area under the curve over 2 h 120.6 and 132.9, respectively; Pmaxfor all other positive subjective effects (good drug effects, overall drug liking, and take drug again VAS scores) compared with MS (Pmax) and median time to Cmaxfor morphine following administration of MSN and MS were similar (27.3 ng/mL and 0.57 h versus 27.7 ng/mL and 0.6 h, respectively). Naltrexone mean Cmaxwas 1497 pg/mL after MSN and median time to Cmaxwas 0.55 h.CONCLUSIONS: When crushed and administered intranasally, MSN was associated with significantly lower ratings of drug liking and other positive subjective effects compared with MS.

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Beatrice Setnik,1 Carl L Roland,1 Kenneth W Sommerville,1,2 Glenn C Pixton,1 Robert Berke,3,4 Anne Calkins,5 Veeraindar Goli1,2 1Pfizer Inc, 2Duke University Medical Center, Durham, NC, USA; 3Family Health Medical Services PLLC, Mayville, 4Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, 5New York Spine & Wellness Center, Syracuse, NY, USA Objective: To evaluate the conversion of opioid-experienced patients with chronic moderate-to-severe pain to extended-release morphine sulfate with sequestered naltrexone hydrochloride (MSN) using a standardized conversion guide. Methods: This open-label, single-arm study was conducted in 157 primary care centers in the United States. A total of 684 opioid-experienced adults with chronic moderate-to-severe pain were converted to oral administration of MSN from transdermal fentanyl and oral formulations of hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and other morphine products using a standardized conversion guide. The primary endpoint was the percentage of patients achieving a stable MSN dose within a 6-week titration phase. Secondary endpoints included duration of time to stable dose, number of titration steps, safety and efficacy measures, and investigator assessment of conversion guide utility. Results: Of the 684 patients, 51.3% were converted to a stable dose of MSN (95% confidence interval: 47.5%, 55.1%). The mean (standard deviation) number of days to stable dose was 20 (8.94), and number of titration steps to stable dose was 2.4 (1.37). The majority of adverse events were mild/moderate and consistent with opioid therapy. Mean pain scores at stable dose decreased from baseline. Investigators were generally satisfied with the conversion guide and, in 94% of cases, reported they would use it again. Conclusion: Conversion to MSN treatment using the standardized MSN conversion guide was an attainable goal in approximately half of the population of opioid-experienced patients with chronic moderate-to-severe pain. Investigators found the guide to be a useful tool to assist conversion of opioid-experienced patients to MSN. Keywords: opioid conversion, rotation, morphine, primary care, safety, equianalgesic

Purpose: Loving-kindness meditation has been used for centuries in the Buddhist tradition to develop love and transform anger into compassion. This pilot study tested an 8-week loving-kindness program for chronic low back pain patients. Method: Patients (N = 43) were randomly assigned to the intervention or standard care. Standardized measures assessed patients’ pain, anger, and psychological distress. Findings: Post and follow-up analyses showed significant improvements in pain and psychological distress in the loving-kindness group, but no changes in the usual care group. Multilevel analyses of daily data showed that more loving-kindness practice on a given day was related to lower pain that day and lower anger the next day. Conclusions: Preliminary results suggest that the loving-kindness program can be beneficial in reducing pain, anger, and psychological distress in patients with persistent low back pain. Implications: Clinicians may find loving-kindness meditation helpful in the treatment of patients with persistent pain.

Clinical observations suggest that many patients with chronic pain have difficulty forgiving persons they perceive as having unjustly offended them in some way. By using a sample of 61 patients with chronic low back pain, this study sought to determine the reliability and variability of forgiveness assessments in patients and to examine the relationship of forgiveness to pain, anger, and psychological distress. Standardized measures were used to assess patients' current levels of forgiveness, forgiveness self-efficacy, pain, anger, and psychological distress. Results showed that forgiveness-related constructs can be reliably assessed in patients with persistent pain, and that patients vary considerably along dimensions of forgiveness. Furthermore, correlational analyses showed that patients who had higher scores on forgiveness-related variables reported lower levels of pain, anger, and psychological distress. Additional analyses indicated that state anger largely mediated the association between forgiveness and psychological distress, as well as some of the associations between forgiveness and pain. These findings indicate that forgiveness can be reliably assessed in patients with persistent pain, and that a relationship appears to exist between forgiveness and important aspects of living with persistent pain.This preliminary study suggests there is a relationship between forgiveness and pain, anger, and psychological distress in patients with chronic low back pain. Patients who report an inability to forgive others might be experiencing higher pain and psychological distress that are mediated by relatively higher levels of state anger.

To evaluate the efficacy and safety of 6 weeks of venlafaxine extended-release (ER) (75 mg and 150-225 mg) treatment in patients with painful diabetic neuropathy. This multicenter, double-blind, randomized, placebo-controlled study included 244 adult outpatients with metabolically stable type 1 or 2 diabetes with painful diabetic neuropathy. Primary efficacy measures were scores on the daily 100 mm Visual Analog Pain Intensity (VAS-PI) and Pain Relief (VAS-PR) scales. Secondary efficacy measures included the Clinical Global Impressions-Severity of Illness and the Clinical Global Impressions-Improvement, Patient Global Rating of Pain Relief, and percentage of patients achieving 50% reduction in pain intensity. Baseline pain intensity was 68.7 mm (moderately severe). At week 6, the percentage reduction from baseline in VAS-PI was 27% (placebo), 32% (75 mg), and 50% (150-225 mg; P < 0.001 vs placebo). Mean VAS-PR scores in the 150-225 mg group were significantly greater than placebo at week 6 (44 vs 60 mm; P < 0.001). The number needed to treat (NNT) for 50% pain intensity reduction with venlafaxine ER 150-225 mg was 4.5 at week 6. Nausea and somnolence were the most common treatment-emergent adverse events. Seven patients on venlafaxine had clinically important ECG changes during treatment. Venlafaxine ER appears effective and safe in relieving pain associated with diabetic neuropathy. NNT values for higher dose venlafaxine ER are comparable to those of tricyclic antidepressants and the anticonvulsant gabapentin.

Purpose A diazepam auto‐injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS (ClinicalTrials.gov identifier NCT00319501). Methods In this phase III, randomized, double‐blind, parallel‐group, placebo‐controlled, multicenter study, subjects with epilepsy on a stable antiepileptic drug regimen who required intermittent medical intervention to control ARS were randomized 1:1 to the placebo AI or the diazepam AI group. Subjects were stratified according to age (2–5, 6–11, ≥12 years). Dose (5, 10, 15, or 20 mg) was based on age and weight. A single dose of study medication was dispensed to be administered by caregivers in an outpatient setting when required. The primary end point was time to next seizure or rescue from 15 min to 12 h postdose. Secondary end points included rescue medication use, number of seizures postdose, caregiver and physician treatment assessments, and safety measures. Key findings Of 234 subjects randomized, 81/110 in the placebo AI group and 82/124 in the diazepam AI group were included in the intent‐to‐treat analysis. Baseline characteristics were similar for both groups. Time to next seizure or rescue was significantly longer in the diazepam AI group compared with the placebo AI group, with a hazard ratio of 0.55 (95% confidence interval [CI] 0.34–0.88; p = 0.012) for diazepam AI versus placebo AI, adjusted for age group. The 25th percentile for time to the next seizure or rescue was 1.18 h (95% CI 0.38–2.03) for placebo AI and 2.70 h (95% CI 0.48–11.42) for diazepam AI; the median was 5.9 h for placebo AI and was inestimable for diazepam AI due to the low number of events experienced by subjects in that group. The proportion of subjects using rescue medication postdose was 30% (24/81) placebo AI versus 17% (14/82) diazepam AI (p = 0.066). An event (seizure or rescue) occurred in 55.6% of subjects in the placebo AI group and 35.4% in the diazepam AI group. The number of seizures experienced during the 12‐h postdose period was significantly lower for diazepam AI (median 0.0) compared with placebo AI (median 1.0; p = 0.010). Treatment‐emergent adverse events (TEAEs) were reported in 44% (35/79) of subjects in the placebo AI group and 42% (34/81) in the diazepam AI group. The most common TEAEs reported were injection site pain (15% placebo AI, 17% diazepam AI) and injection site hemorrhage (6% placebo AI, 5% diazepam AI). Significance The diazepam AI was significantly more effective than placebo AI at delaying the next seizure or rescue. Secondary efficacy end points were generally supportive of the primary outcome. Diazepam AI administered by trained caregivers was effective for the treatment of ARS and was well tolerated, with a safety profile similar to placebo.

Oral opioids have been the mainstay of treatment for acute and chronic pain conditions for hundreds of years, but are fraught with side effects and addiction issues that limit their utility. Since the discovery of morphine as the active ingredient of opium 200 years ago, several synthetic and semisynthetic opioids have shown modest improvement in safety but so far the manipulation of the opioid molecule to target the analgesic effects and block the euphoric and addictive effects have been elusive. The majority of currently available opioids in clinical practice have been the MOP ligands. This chapter explores the oral opioids in preclinical development and in clinical practice and discusses several promising MOP, KOP and DOP ligands in preclinical development and attempts to stress the nuances of treating pain with opioids and the importance of a patient centred approach and a seamless integration between researchers and clinicians.

Pain is a complex phenomenon. In order to understand pain perception one must attempt to understand pain physiology and how certain physiologic and biomedical changes associated with aging may influence the elderly person's pain perception. Understanding the varied changes that occur with aging is very important in diagnosing and managing pain in the elderly population.

Background Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here. Methods Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography. Results Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h). Conclusions Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.

OBJECTIVE The purpose of the present study was to examine factors that influence individual differences in treatment response after multidisciplinary pain management. DESIGN Pre-post assessment design. PATIENTS 119 chronic pain inpatients. MAIN MEASURES Outcome measures included pain report from the McGill Pain Questionnaire, emotional distress from the Symptom Checklist-90 Revised, and activity discomfort from the Activity Discomfort Scale. Process measures included the Family Environment Scale, the Coping Strategies Questionnaire, and the Inventory of Negative Thoughts in Response to Pain. RESULTS Results indicated that pretreatment family environment, cognitive coping strategies, and negative thinking accounted for small yet significant proportions of the variance in outcome. The proportion of variance accounted for by the changes in cognitive coping and negative thinking was somewhat higher. An increase in pain control and rational thinking was related to decreases in depression and anxiety, pain report, and activity discomfort. Decreases in negative social cognitions were related to decreased depression at posttreatment. CONCLUSIONS Changes in coping strategies and negative thinking may be important mechanisms related to improvement, or lack of improvement, in a range of outcome measures. Patients from families who are controlling and disorganized, and patients high on negative thinking at pretreatment may represent high-risk groups in need of further individually tailored interventions.

Fifty-three hospitalized elderly men with medical illness were diagnosed with major depressive disorder and followed up for a mean of 2.3 months. Documentation and management of the depression by medical housestaff during the followup period were examined. There was no note of depression in the medical records of 44% of depressed patients, and depression was on the active problem list of only 32%. Followup and management plans for the depression after discharge were documented in 29%. No form of treatment was prescribed for 44% of depressed patients. Outcomes were determined by psychiatric evaluation at the end of the followup period. Of the 33 patients still alive and evaluated at followup, 64% had persistent depression, 18% improved, and 18% were in complete remission. No baseline patient sociodemographic or health characteristic, including severity of depression, was significantly related to improvement. Likewise, neither extent of documentation nor treatment implemented by housestaff was a significant predictor of outcome. We conclude that serious clinical depression in medically ill older patients may persist for a considerable period after hospital discharge and neither detection nor current management strategies appear to have a major impact on outcome.

The authors validate the usefulness of the Diagnostic Interview Schedule (DIS) in prevalence studies of major depression (MD) in medically ill male veterans. The affective disorders portion of the DIS was administered by a trained interviewer to a representative sample of 408 medically-ill hospitalized patients (75% over age 70). Using a standardized handscoring method for the DIS, the patients were categorized as having 01 not having MD. Using a two-stage design, sixty-nine patients scoring above a cutoff score on a self-rated depression scale were referred for blind evaluation by a psychiatrist. The psychiatrist made a clinical diagnosis of MD using a standard checklist of DSM-III criteria. The DIS correctly diagnosed MD in 78 percent (14/18) of older and 69 percent (9/13) of younger patients, and correctly ruled out the disorder in 65 percent (15/23) of older and 67 percent (10/15) of younger patients; the kappa statistic of agreement was .40 in older and .36 in younger patients.

Dramatic relief of pain and life-altering changes in quality of life in some patients treated with immunomodulators such as thalidomide compel us to look more closely at unconventional mechanisms that may be involved in propagation of persistent pain. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 are the cytokines with the most evidence in pain modulation. TNF-alpha and IL-1beta seem to initiate neuropathic pain, IL-6 maintains such pain, and IL-10 inhibits this persistent pain. Thalidomide was found to be effective in animal models by inhibiting TNF-alpha production. Several case reports and case series in humans have demonstrated mixed results, with some patients having dramatic responses, especially in chronic intractable conditions such as complex regional pain syndrome. Thalidomide may be an alternative for some patients with intractable pain. However, use of thalidomide is limited by its neurotoxic and teratogenic effects. Newer analogues may significantly improve the risk/benefit of using such immunomodulators.

OBJECTIVE: To study the epidemiology of depressive disorder in younger and older medical inpatients. DESIGN, PATIENTS, & SETTING: Depressive disorders were examined using the Diagnostic Interview Schedule in 116 young and 332 elderly medically ill men hospitalized in a VA medical center. RESULTS: Major depressive disorder was diagnosed in 22.4% of men under 40 and 13.3% of those age 70 or over; minor depression was found in 18.1% of young and 29.2% of older men. Besides age, other risk factors for major depression were impaired social support, severe medical illness or functional disability in older men, and history of psychiatric problems primarily in younger men; specific medical diagnosis was not a risk factor. Major depression was associated with more severe symptomatology in younger patients; in both age groups, however, symptoms were of prolonged duration and frequently included suicidal thoughts. CONCLUSIONS: Depressive disorder in hospitalized male veterans is common, varies with age, severity of medical illness, degree of social support, and history of psychiatric problems and is associated with considerable psychological morbidity. Language: en

The authors conducted a clinical trial to examine the efficacy and safety of nortriptyline in the treatment of major depression in elderly medical inpatients. The diagnosis of major depression was made by a psychiatrist in 41 of 680 patients 65 years of age or older. The study was balted at the midpoint because of inadequate patient recruitment, primarily a consequence of medical illnesses that prevented more than 80% of eligible patients from participating in or completing the clinical trial. Major or minor medical contraindications to the use of antidepressants were present in over 90% of depressed patients. Short-term follow-up was conducted on untreated depressed patients, those receiving antidepressants at the time of assessment, and those in whom antidepressant treatment was initiated after assessment. Non-randomized exposure to antidepressants did not predict remission of depression at follow-up due to spontaneous remission in the untreated group. Given the prevalence of medical contraindications to antidepressant use among depressed elderly patients and the problems with side effects in treated patients, there were few depressed, elderly hospitalized patients who were candidates for antidepressant therapy.

Chronic pain has been considered as a variant of depression or as a masked depression. In an attempt to unravel the complex relationship between chronic pain and depression, we administered the TRH stimulation test to a uniform group of chronic pain patients classified into those with and without major depression using DSM-III criteria. Eighteen percent showed blunting of TSH response to TRH. There was no significant difference between the two groups.

Forty-one elderly medical inpatients with active major depression were matched with nondepressed controls from the same population. Survival and health care utilization were examined during a mean follow-up period of five months. Cases and controls were matched by age, functional status, severity and type of medical illness, and extent of disease. In-hospital mortality was significantly higher among depressed compared with nondepressed controls (6 vs 0 deaths, P = .03). For patients discharged from the hospital alive, however, depression did not have a substantial impact on mortality (31.4% cases, 31.7% controls). Health care utilization--in terms of days of inpatient care--was significantly higher both during the index admission (25 vs 14 days, P less than .005) and during the follow-up period (16 vs 7 days, P less than .05) for depressed patients compared with controls. Hence, older medically ill patients with major depression consume more healthcare resources and experience greater mortality during their initial hospital stay. After discharge, while survival is little affected, excess resource utilization persists among those with depression.

Bradley et al. (1984) reported that 30% of patients over the age of 60 demonstrate leukoencephalopathy or patchy, deep white matter lesions (PWML) of abnormal signal intensity on T2 weighted images on magnetic resonance imaging (MRI). These foci, which are not seen in normal individuals below the age of 45 (George et al. 1986b), are believed to be a function of the late stage of the aging process. With MRI, areas of deep white matter foci resemble those seen in known cerebral infarction (Erkinjuntti et al. 1984) and are reported to correspond to areas of moderate to severe arteriolar hyalinization and rarefaction on pathological examination (George et al. 1986a). The overall perspective on the clinical significance of PWML has yet to be determined. In patients with Alzheimer’s disease, the prevalence and severity of PWML is increased (Bent-~wad~i et al. 1985; George et al. 1986b). Prevalence of PWML of 36.67% was found in patients with Alzheimer’s disease at our medical center (mean age 64.3 years) (Heyman et al. 1986). Post (1962) and Roth (1986) suggested that the increased prevalence and severity of depressive illness and suicide in middle and late life is due to subtle cerebral (primarily vascular) changes correlated with aging. As PWML may reflect early and subtle alterations in cerebral function, we decided to assess the relationship, if any, between the occurrence of PWML (leuk~nceph~opa~y) and depression, especially depression in middle and late life. We also examined the relationship between PWML and early-onset affective disorder (i.e., onset of first episode before the age of 45) and affective disorder that first occurs after the age of 45. We used 45 years as the cutoff for the study because of the report that PWML are not seen in normal individuals below the age of 45 (George et al. 1986b). We also examined the hypothesis that the incidence of PWML would be higher in patients with the first episode of affective disorder above age 45 than in those patients above 45 with affective disorder that started before the age of 45. Such a finding would suggest that PWML may be causally related to depression in some of these individuals.