Opioid analgesics are recognized as a legitimate medical therapy for selected patients with severe chronic pain that does not respond to other therapies. However, opioids are associated with risks ...for patients and society that include misuse, abuse, diversion, addiction, and overdose deaths. Therapeutic success depends on proper candidate selection, assessment before administering opioid therapy, and close monitoring throughout the course of treatment. Risk assessment and prevention include knowledge of patient factors that may contribute to misuse, abuse, addiction, suicide, and respiratory depression. Risk factors for opioid misuse or addiction include past or current substance abuse, untreated psychiatric disorders, younger age, and social or family environments that encourage misuse. Opioid mortality prevalence is higher in people who are middle aged and have substance abuse and psychiatric comorbidities. Suicides are probably undercounted or frequently misclassified in reports of opioid-related poisoning deaths. Greater understanding and better assessment are needed of the risk associated with suicide risk in patients with pain. Clinical tools and an evolving evidence base are available to assist clinicians with identifying patients whose risk factors put them at risk for adverse outcomes with opioids.
ABSTRACT
Objective. To provide clinicians with a brief screening tool to predict accurately which individuals may develop aberrant behaviors when prescribed opioids for chronic pain.
Design. One ...hundred and eighty‐five consecutive new patients treated in one pain clinic took the self‐administered Opioid Risk Tool (ORT). The ORT measured the following risk factors associated in scientific literature with substance abuse: personal and family history of substance abuse; age; history of preadolescent sexual abuse; and certain psychological diseases. Patients received scores of 0–3 (low risk), 4–7 (moderate risk), or ≥ 8 (high risk), indicating the probability of their displaying opioid‐related aberrant behaviors. All patients were monitored for aberrant behaviors for 12 months after their initial visits.
Results. For those patients with a risk category of low, 17 out of 18 (94.4%) did not display an aberrant behavior. For those patients with a risk category of high, 40 out of 44 (90.9%) did display an aberrant behavior. The authors used the c statistic to validate the ORT, because it simultaneously assesses sensitivity and specificity. The ORT displayed excellent discrimination for both the male (c = 0.82) and the female (c = 0.85) prognostic models.
Conclusion. In a preliminary study, among patients prescribed opioids for chronic pain, the ORT exhibited a high degree of sensitivity and specificity for determining which individuals are at risk for opioid‐related, aberrant behaviors. Further studies in a variety of pain and nonpain settings are needed to determine the ORT's universal applicability.
A paucity of corroborative psychological and psychiatric evidence may be inhibiting detection of drug intoxication suicides in the United States. We evaluated the relative importance of suicide notes ...and psychiatric history in the classification of suicide by drug intoxication versus firearm (gunshot wound) plus hanging/suffocation-the other two major, but overtly violent methods.
This observational multilevel (individual/county), multivariable study employed a generalized linear mixed model (GLMM) to analyze pooled suicides and undetermined intent deaths, as possible suicides, among the population aged 15 years and older in the 17 states participating in the National Violent Death Reporting System throughout 2011-2013. The outcome measure was relative odds of suicide versus undetermined classification, adjusted for demographics, precipitating circumstances, and investigation characteristics.
A suicide note, prior suicide attempt, or affective disorder was documented in less than one-third of suicides and one-quarter of undetermined deaths. The prevalence gaps were larger among drug intoxication cases than gunshot/hanging cases. The latter were more likely than intoxication cases to be classified as suicide versus undetermined manner of death (adjusted odds ratio OR, 41.14; 95% CI, 34.43-49.15), as were cases documenting a suicide note (OR, 33.90; 95% CI, 26.11-44.05), prior suicide attempt (OR, 2.42; 95% CI, 2.11-2.77), or depression (OR, 1.61; 95% CI, 1.38 to 1.88), or bipolar disorder (OR, 1.41; 95% CI, 1.10-1.81). Stratification by mechanism/cause intensified the association between a note and suicide classification for intoxication cases (OR, 45.43; 95% CI, 31.06-66.58). Prior suicide attempt (OR, 2.64; 95% CI, 2.19-3.18) and depression (OR, 1.48; 95% CI, 1.17-1.87) were associated with suicide classification in intoxication but not gunshot/hanging cases.
Without psychological/psychiatric evidence contributing to manner of death classification, suicide by drug intoxication in the US is likely profoundly under-reported. Findings harbor adverse implications for surveillance, etiologic understanding, and prevention of suicides and drug deaths.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Opioid‐Induced Constipation Webster, Lynn R.
Pain medicine (Malden, Mass.),
October 2015, Volume:
16, Issue:
S1
Journal Article
Peer reviewed
Open access
Introduction
Opioid‐induced constipation (OIC) is common in people treated with opioids and poses risks for physical sequelae, analgesic discontinuation, and decreased quality of life.
Methods
...Targeted literature review of evidence‐ and consensus‐based data on appropriate diagnosis, concise definition, and conventional and newer management strategies for OIC.
Results
OIC may develop early and need early treatment. To address gaps in consistent definitions and treatment recommendations, a consensus panel organized through the American Academy of Pain Medicine Foundation set diagnostic criteria and endorsed the Bowel Function Index for OIC assessment. The panel further proposed management strategies for OIC, including a proposed threshold for prescriptive therapies.
Discussion
OIC results from action exerted on opioid receptors in the gastrointestinal tract, a mechanism distinct from idiopathic constipation. Lifestyle changes and over‐the‐counter drugs are first‐line treatments but leave refractory constipation in many opioid‐treated patients. Newer therapeutic modalities that are available and in development are highlighted.
Summary
Physicians need a better understanding of the negative impacts of OIC for patients and better OIC‐specific methods to assess, treat, and monitor it.
This multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain.
Adults with opioid-induced ...constipation (OIC; <3 spontaneous bowel movements SBMs per week) were randomized 1:1 to double-blind lubiprostone 24 μg or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (≥1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (≥3 SBMs per week) for at least 9 of the 12 treatment weeks.
In total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7 h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone.
Lubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.
Objective
To better characterize safety profiles associated with the intrathecal (IT) administration of morphine and ziconotide and discuss how they relate to mechanisms of action.
Methods
Published ...data were evaluated to identify potential relationships between safety profiles of IT morphine and IT ziconotide and their mechanisms of action.
Results
Potentially severe and clinically relevant adverse events (AEs) associated with IT morphine include respiratory depression, tolerance, and granuloma formulation, whereas IT ziconotide is associated with neuropsychiatric AEs, such as cognitive impairment, hallucinations, and changes in mood or consciousness, particularly with high doses and rapid titration. AEs associated with these IT therapies may result from spread of the medication out of the IT space into areas of the central and peripheral nervous systems and systemic circulation. AEs that occur usually can be managed and, in some cases, prevented. To mitigate risk, patients' histories should be reviewed to identify potential complicating factors (e.g., obesity or other risk factors for respiratory dysfunction in patients receiving IT morphine; a history of psychosis in patients receiving IT ziconotide). Also, treatment should be initiated at a low dose, titrated slowly, and patients should be closely monitored during treatment.
Conclusions
IT morphine and IT ziconotide are approved by the US Food and Drug Administration for patients who do not respond to less invasive treatments, but the safety profiles of each may make them more or less appropriate for certain patient populations.
The long-term safety of naldemedine, a peripherally acting µ-opioid receptor antagonist, was evaluated in patients with opioid-induced constipation and chronic noncancer pain in a 52-week, ...randomized, double-blind, phase 3 study. Eligible adults who could be on a routine laxative regimen were randomized 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 623) or placebo (n = 623). The primary endpoint was summary measures of treatment-emergent adverse events (AEs). Additional endpoints included opioid withdrawal on the Clinical Opiate Withdrawal Scale and the Subjective Opiate Withdrawal Scale, pain intensity on Numeric Rating Scale, frequency of bowel movements, and constipation-related symptoms and quality of life on the Patient Assessment of Constipation Symptoms and Patient Assessment of Constipation Quality of Life scales, respectively. Treatment-emergent AEs (naldemedine, 68.4% vs placebo, 72.1%; difference: -3.6% 95% confidence interval: -8.7 to 1.5) and treatment-emergent AEs leading to study discontinuation (6.3% vs 5.8%; difference: 0.5% -2.2 to 3.1) were reported for similar proportions of patients. Diarrhea was reported more frequently with naldemedine (11.0%) vs placebo (5.3%; difference: 5.6% 2.6-8.6). There were no meaningful differences between groups in opioid withdrawal or pain intensity. Sustained significant improvements in bowel movement frequency and overall constipation-related symptoms and quality of life were observed with naldemedine (P ≤ 0.0001 vs placebo at all time points). Naldemedine was generally well tolerated for 52 weeks and did not interfere with opioid-mediated analgesia or precipitate opioid withdrawal. Naldemedine significantly increased bowel movement frequency, improved symptomatic burden of opioid-induced constipation, and increased patients' quality of life vs placebo.
Abstract
Objective
This study evaluated the efficacy and safety of oral naldemedine 0.1 mg, 0.2 mg, or 0.4 mg once daily in patients who had opioid-induced constipation (OIC) and maintained a stable ...laxative regimen.
Methods
This four-week, phase 2b, randomized, double-blind placebo-controlled trial (clinicaltrials.gov identifier NCT01443403) enrolled patients on long-term opioid therapy for chronic noncancer pain with OIC. The primary efficacy end point was change in weekly spontaneous bowel movement (SBM) frequency from baseline to the last two weeks of treatment. Secondary end points included the proportion of SBM responders (patients with ≥3 SBMs/week and an increase of ≥1 SBM/week from baseline over the last 2 weeks of treatment). Safety parameters assessed included adverse events, effects on analgesia, and opioid withdrawal symptoms.
Results
Overall, 244 patients were randomized 1:1:1:1 to naldemedine 0.1 mg, 0.2 mg, 0.4 mg, or placebo. Baseline patient characteristics were comparable. Weekly SBM frequency was significantly higher with naldemedine 0.2 mg (3.37, P = 0.0014) and 0.4 mg (3.64, P = 0.0003), but not with 0.1 mg (1.98, P = 0.3504), vs placebo (1.42). The proportion of SBM responders was significantly higher with naldemedine 0.2 mg (71.2%, P = 0.0005) and 0.4 mg (66.7%, P = 0.003), but not with 0.1 mg (52.5%, P = 0.1461), vs placebo (39.3%). Treatment-emergent adverse events were generally mild to moderate in severity; incidences increased with naldemedine dose. No clinically meaningful changes in other safety parameters were observed.
Conclusion
Naldemedine 0.2 mg once daily is the optimal dose for future confirmatory trials in OIC.
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