Kappa opioid receptor antagonism: Are opioids the answer for treatment resistant depression?

Introduction: Past trials of buprenorphine (BUP) in the treatment of major depressive disorder (MDD) have displayed favorable results, although its clinical utility was limited by the risk of abuse or physical dependence. By combining BUP with samidorphan (SAM), the euphoric high is negated by an opposing mechanism, which theoretically reduces addictive-like properties while allowing the antidepressant properties to remain. As such, the objective of this article is to analyze the results of BUP/SAM premarketing clinical trials as adjunctive treatment for treatment-resistant MDD. Methods: A comprehensive PubMed/MEDLINE search was conducted through November 9, 2017, using the following search terms: depression, samidorphan, buprenorphine, ALKS-5461. Additional data were obtained from Clinicaltrials.gov and resources included in the present study. All English-language clinical trials evaluating the combination of BUP/SAM in the treatment of MDD were included. Results: A few premarketing studies have evaluated the efficacy and safety of BUP/SAM combination as adjunctive treatment in patients with treatment-resistant MDD. The FORWARD-1 through FORWARD-5 trials concluded (1) the most effective dosing ratio of BUP/SAM to reduce abuse potential was 1:1; (2) statistically significant changes in scores from baseline on the Montgomery-Asberg Depression Rating Scale were noted for the 2 mg/2 mg dose compared with placebo; and (3) the most commonly reported adverse effects were nausea, dizziness, and fatigue. Discussion: Buprenorphine/samidorphan has shown favorable results for efficacy and tolerability in premarketing studies evaluating its use as adjunctive therapy for treatment-resistant MDD. Its novel mechanism targeting the opioid pathway may serve as a promising antidepressant devoid of abuse potential

Characterization of hospitalized patients who received naloxone while receiving opioids with or without gabapentinoids

Introduction: Gabapentin and pregabalin (gabapentinoids) can be given with opioids for opioid-sparing and adjuvant analgesic effects. In the context of certain comorbidities and high dosages, coadministration of these agents can lead to respiratory depression or oversedation, necessitating naloxone administration. Methods: A retrospective chart review from January 2015 to December 2017 was conducted to include patients who received naloxone and opioids with or without gabapentinoids. Exclusion criteria included pregnancy or having received naloxone in the emergency department, intensive care, or pediatrics units. The primary outcome was to characterize differences between groups regarding comorbidities, history of renal or hepatic dysfunction, history of SUD, opioid tolerance, initiation and dose appropriateness of gabapentinoids, and dose intensity of gabapentinoids and opioids. Secondary outcomes were concomitant CNS depressant use and naloxone episodes for documented respiratory depression. Results: Of 126 patients who met inclusion criteria, 36 received opioids and gabapentinoids (gabapentinoid group) and 90 received opioids alone (nongabapentinoid group). There were 136 naloxone episodes between the 2 groups. More than 50% of the naloxone episodes in the gabapentinoid group involved opioids of at least 90 oral morphine mg equivalents. Respiratory depression accounted for 39% and 15.8% of the naloxone episodes in the gabapentinoid and nongabapentinoid groups, respectively. Discussion: There may be increased naloxone episodes among patients receiving opioids and gabapentinoids. Future studies are needed to evaluate the incremental risk of respiratory depression and oversedation as it pertains to concomitant medication administration and patient-specific factors

Gabapentin for Off-Label Use: Evidence-Based or Cause for Concern?

Gabapentin is widely used in the United States for a number of off-label indications, often as an alternative to opioid therapy. Increasing evidence has emerged suggesting that gabapentin may not be as benign as once thought and may be associated with substance abuse in concert with opioids. With concerns for safety mounting, it is prudent to examine the efficacy of gabapentin across its many uses to understand the risk-benefit balance. Reviews on off-label indications such as migraine, fibromyalgia, mental illness, and substance dependence have found modest to no effect on relevant clinical outcomes. This high-quality evidence has often been overshadowed by uncontrolled studies and limited case reports. Furthermore, the involvement of gabapentin in questionable marketing schemes further calls its use into question. Overall, clinicians should exercise rigorous appraisal of the available evidence for a given indication, and researchers should conduct larger, higher-quality studies to better assess the efficacy of gabapentin for many of its off-label uses

Gabapentinoid Pharmacology in the Context of Emerging Misuse Liability

This article will review the epidemiology and pharmacology of gabapentinoids (gabapentin and pregabalin) relevant to their emerging misuse potential and provide guidance for clinical and regulatory management. Gabapentinoids are γ-aminobutyric acid analogues that produce their therapeutic effects by inhibiting voltage-gated calcium channels and decreasing neurotransmitter release. Recently gabapentinoid prescribing and use have increased tremendously. Although traditionally thought to possess a favorable safety profile, gabapentinoid misuse has also risen significantly. Gabapentinoid misuse generally occurs in combination with other substances, most notably opioids, and may be for purposes of eliciting euphoric effects, enhancing the effects of other substances, or self-treating conditions such as withdrawal, pain, anxiety, or insomnia. Given its faster onset, increased bioavailability and potency, and nonsaturable absorption, pregabalin\u27s pharmacokinetics theoretically enhance its misuse liability versus gabapentin. However, gabapentin can produce similar euphoric effects, and epidemiologic studies have identified higher rates of gabapentin misuse in the United States, likely because of greater availability and less regulated prescribing. Although adverse events of gabapentinoid-only ingestion are relatively benign, a growing body of evidence indicates that gabapentinoids significantly increase opioid-related morbidity and mortality when used concomitantly. In addition, significant withdrawal effects may occur on abrupt discontinuation. As a result of these trends, several US states have begun to further regulate gabapentinoid prescribing, reclassifying it as a controlled substance or mandating reporting to local prescription drug-monitoring programs. Although increased regulation of gabapentin prescribing may be warranted, harm reduction efforts and increased patient and provider education are necessary to mitigate this concerning gabapentinoid misuse trend

Use of power-law analysis to predict abuse or diversion of prescribed medications: proof-of-concept mathematical exploration

Abstract Objective To conduct a proof-of-concept study comparing Lorenz-curve analysis (LCA) with power-law (exponential function) analysis (PLA), by applying segmented regression modeling to 1-year prescription claims data for three medications—alprazolam, opioids, and gabapentin—to predict abuse and/or diversion using power-law zone (PLZ) classification. Results In 1-year baseline observation, patients classified into the top PLZ groups (PLGs) were demographically and diagnostically similar to those in Lorenz-1 (top 1% of utilizers) and Lorenz-25 (top 25%). For prediction of follow-up (6-month post-baseline) Lorenz-1 use of alprazolam and opioids (i.e., potential abuse/diversion), PLA had somewhat lower sensitivity compared with LCA (83.5–95.4% vs. 99.5–99.9%, respectively) but better specificity (98.2–98.8% vs. 75.5%) and much better positive predictive value (PPV; 34.5–45.3% vs. 4.0–4.6%). Of top-PLG alprazolam- and opioid-treated patients, respectively, 20.7 and 9.9% developed incident (new) Lorenz-1 in followup, compared with < 3% of Lorenz-25 patients. For gabapentin, neither PLA nor LCA predicted incident Lorenz-1 (PPV = 0.0–1.4%). For all three medications, PLA sensitivity for follow-up hospitalization was < 5%, but specificity was better for PLA (97.3–99.2%) than for LCA (74.3–75.4%). PLA better identified patients at risk of future controlled substance abuse/diversion than did LCA, but the technique needs refinement before widespread use

Receipt of Substance Use Counseling Among Ambulatory Patients Prescribed Opioids in the United States

Background: As opioid-related overdose deaths climb in the U.S., risk reduction measures are increasingly important. One such measure recommended involves provision of proactive substance use counseling regarding the risks of opioid analgesics. This is particularly important in patients at increased risk of overdose, such as those with substance use disorders (SUD) or those receiving concomitant medications that further increase the overdose risk (eg, benzodiazepines, gabapentinoids, or Z-hypnotics). However, previous research regarding the likelihood that such counseling is provided during outpatient prescriber visits is lacking. Objectives: To determine the percentage of U.S. ambulatory care visits in which patients taking prescription opioids received substance use counseling, and whether counseling was more common in patients with concomitant GABAergic medication(s) (benzodiazepine, gabapentinoid or Z-hypnotic) or substance use disorder (SUD) diagnosis. Methods: A cross-sectional analysis was conducted of all patients aged ⩾18 years identified as having a prescription opioid on their medication list within the 2014-2015 National Ambulatory Medical Care Survey data. Results: Among 162.7 million visits in which patients were taking opioid medication(s), substance use counseling was provided in 2.4%. During visits for patients receiving opioid(s) plus GABAergic(s), substance use counseling was marginally more common (3.1% versus 2.0%, P \u3c.0001). Substance use counseling was also more common among visits for patients taking opioid(s) with SUD (18.9% versus 1.5%, P \u3c.0001). Among visits in which a patient was diagnosed with SUD and taking opioid(s) plus GABAergic(s), counseling was more common (23.1% versus 1.4%, P \u3c.0001) compared to patients taking opioid(s) plus GABAergic(s) without SUD. Conclusions: Among national ambulatory care visits in the United States, substance use counseling is provided infrequently for patients taking opioids, even when significant risk factors are present. Increasing patient education may help reduce opioid-related overdose mortality