Outcomes associated with once-daily versus multiple-daily dosing of buprenorphine/naloxone for opioid use disorder.

BACKGROUND AND OBJECTIVES: Clinical studies examining once-daily versus multiple-daily dosing of buprenorphine/naloxone in patients with opioid use disorder (OUD) in the absence of comorbid pain are lacking. METHODS: This retrospective chart review aimed to compare 100 patients prescribed single-daily buprenorphine/naloxone (n = 50) to those prescribed multiple-daily buprenorphine/naloxone (n = 50) to elucidate the impact that dosing frequency has on negative urine drug screens (UDS) and the number of relapses in OUD. RESULTS: The once-daily cohort produced 84% negative UDSs compared with 74% in the multiple-daily cohort which was statistically significant (p = .034). There were a total of 43 relapses reported in the once-daily cohort, compared with 141 relapses in the multiple-daily cohort (p < .001). The average number of relapses per patient in the single-daily cohort was 0.68 compared with the multiple-daily cohort average of 2.16 (p < .001). In the once-daily cohort, 14% of patients experienced at least one relapse throughout the study, compared with 31% in the multiple-daily cohort (p < .002). There were no significant differences between time to relapse, adherence to treatment, or treatment retention. Statistically significantly more patients in the multiple-daily cohort were using methamphetamines (p = .005); there were no significant differences between groups with the use of any other illicit or non-prescribed substances. DISCUSSION AND CONCLUSIONS: Once-daily dosing was associated with more negative UDSs and fewer opioid relapses compared with multiple-daily dosing. SCIENTIFIC SIGNIFICANCE: This was the first study to evaluate buprenorphine/naloxone dosing frequency for opioid use disorder, in the absence of chronic pain. Additional studies evaluating optimal dosing schedules for relapse prevention are warranted.

What Are They Thinking? A National Study of Stability and Change in Divorce Ideation.

This study reports on a nationally representative sample of married individuals ages 25-50 (N = 3,000) surveyed twice (1 year apart) to investigate the phenomenon of divorce ideation, or what people are thinking when they are thinking about divorce. Twenty-eight percent of respondents had thought their marriage was in serious trouble in the past but not recently. Another 25% had thoughts about divorce in the last 6 months. Latent Class Analysis revealed three distinct groups among those thinking about divorce at Time 1: soft thinkers (49%), long-term-serious thinkers (45%), and conflicted thinkers (6%). Yet, divorce ideation was not static; 31% of Time 1 thinkers were not thinking about it 1 year later (and 36% of nonthinkers at Time 1 were thinking about it 1 year later). Also, Latent Transition Analysis revealed 49% of Time 1 long-term-serious thinkers, 56% of soft thinkers, and 51% of conflicted thinkers had shifted groups at Time 2, mostly in the direction of less and softer thinking about divorce. Overall, divorce ideation is common but dynamic, and it is not necessarily an indication of imminent marital dissolution.

Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression.

Induction of cutaneous squamous cell carcinoma (SCC) in mice, by topical chemical [9,10-dimethylbenzanthracene (DMBA) and phorbol 12-myristate 13-acetate (PMA)] application, is a multistep process involving papilloma formation and progression to carcinoma. We have generated a transgenic (Tg) mouse [keratin-14 (K14)-survivin] with skin expression of survivin, an inhibitor of apoptosis expressed in most human skin cancers and premalignant lesions. K14-survivin mice were resistant to DMBA-induced keratinocyte apoptosis. To investigate the role of survivin and apoptosis in cutaneous carcinogenesis, mice were treated once topically with DMBA followed by twice weekly with PMA for 32 weeks. Surprisingly, tumor formation was less frequent (31% versus 43%) and significantly delayed (P = 0.01) in K14-survivin mice compared with non-Tg littermates. On the other hand, papilloma regression was not observed in Tg mice, whereas 20% of papillomas regressed in non-Tgs; one SCC was generated in Tg mice, whereas none were seen in non-Tgs. To increase tumor formation and SCC in particular, a second experiment was performed with mice on a p53+/- background. Again, DMBA/PMA-induced tumor formation was less (71% versus 89%) and significantly delayed (P = 0.02) in K14-survivin p53+/- animals compared with p53+/- non-Tgs. Papilloma regression was also not observed in Tg p53+/- mice, whereas 10% of papillomas regressed in p53+/- non-Tgs. The rate of papilloma progression to SCC was 21% in Tg p53+/- mice compared with 12% in p53+/- non-Tgs. Papillomas did not reveal significant differences in mitotic or apoptotic indices. Survivin expression was detected in all of the tumors. These results indicate that despite a paradoxical negative effect on tumor formation, survivin expression prevents papilloma regression and promotes conversion to SCC, consistent with its expression in most skin cancers and their precursors.

Apoptosis regulators and responses in human melanocytic and keratinocytic cells.

Apoptosis in keratinocytes is required for epidermal turnover, stratum corneum formation, and removal of ultraviolet-damaged premalignant cells. Its role in melanocyte homeostasis and transformation, on the other hand, has not been defined, although apoptosis resistance is a commonly recognized feature of melanoma. We examined the expression of apoptosis regulators in melanocytes, keratinocytes, melanoma, and HaCat cells. Melanocytic cells expressed relatively high levels of Bcl-2, Bcl-X(L), Mcl-1, C-IAP-1, C-IAP-2, XIAP, Livin, and Apaf-1. The only apoptotic regulator that was differentially expressed in melanoma cells and not melanocytes was Survivin, whereas Bax was expressed in melanocytes but not in most melanoma lines. Keratinocytic cells, on the other hand, expressed high levels of FLIP and were relatively deficient in Bcl-2 family proteins. Levels of p53 were highest in HaCat cells and some of the melanoma lines, and barely detectable in melanocytes and keratinocytes. Next, susceptibility of these cells types to apoptosis induced by ultraviolet B, the tyrosine analog 4-tert-butylphenol, and cytotoxic drugs was examined. Melanocytes were relatively resistant to ultraviolet B, whereas keratinocytes were unresponsive to 4-tert-butylphenol. Melanocytes and keratinocytes were generally less susceptible than melanoma lines and HaCat cells to etoposide, cisplatin, and staurosporine. Induction of apoptosis in these cell types was generally associated with decreased levels of Mcl-1, XIAP, and Livin, and increased levels of p53, whereas levels of other apoptotic regulators were unaltered. These results provide insights into the potential roles of apoptosis in the function and transformation of epidermal melanocytes and keratinocytes.

UVB-induced apoptosis drives clonal expansion during skin tumor development.

The mechanism by which a single mutant cell clonally expands is usually assumed to involve an additional mutation in a cell cycle regulatory gene. An alternative mechanism for driving clonal expansion is apoptosis, which might create vacant stem cell compartments that can be repopulated by mutant cells. This model predicts that in a mouse with reduced apoptotic capacity (i) more mutated cells will appear initially but (ii) these cells will expand into clones more slowly than in wild-type animals. To test this hypothesis for ultraviolet B (UVB)-induced skin carcinogenesis, we examined UVB-induced p53 mutant clones and tumors in a transgenic (Tg) mouse (K14-Survivin) with skin-specific expression of the apoptosis inhibitor Survivin. To limit the effects of Survivin on apoptosis, without affecting epidermal proliferation or differentiation, we used Survivin expression levels and UVB doses that resulted in a 2-fold reduction in keratinocyte apoptosis. After 5 weeks of chronic UVB irradiation, newly created p53 mutant keratinocyte clones (indicative of initial mutation frequency) were 1.4-fold more frequent in K14-Survivin mice (P = 4 x 10(-6)). As predicted, this effect was reversed for clones growing by clonal expansion, which were rarer in Tg skin by 1.7-fold (P = 0.047). At 10 weeks large expanding Tg clones were rarer by a magnitude approaching the apoptosis differential (approximately 2-fold, P = 4 x 10(-5)). Survivin expression also retarded clonal expansion at later stages of tumor development. By 20 weeks 95% of animals carried tumors (primarily papillomas), which were 1.6-fold rarer in apoptosis-defective Tg mice (P = 0.03). In contrast, the rate of tumors attaining large size (> or =3 mm, P = 0.048) and converting to carcinoma was increased approximately 2-fold in Tg mice. Thus, Survivin-regulated apoptosis appears to suppress two stages that involve new mutations, initiation and malignant conversion, yet drives clonal expansion of existing p53 mutant cells.