Change in opioid and analgesic use for headaches after aneurysmal subarachnoid hemorrhage over time.

BACKGROUND: Severe headache, a hallmark of aneurysmal subarachnoid hemorrhage (aSAH), affects up to 90% of patients during hospitalization. Opioids remain the guideline recommended mainstay of acute therapy despite their significant side effects and potential for tolerance and addiction. We evaluated time trends in opioid prescriptions, hypothesizing a decline with increasing recognition of the opioid crisis. METHODS: We performed a retrospective review of patients with aSAH admitted to a single tertiary care center between 2012 and 2019 and included patients with Hunt-Hess-Grade≤3 who were able to verbalize pain scores. Collected variables included mean and maximum daily headache scores, aneurysm treatment modality, and daily analgesic medication doses. RESULTS: Of 340 patients with aSAH, 114 (86 from 2012-2016 and 28 from 2017-2019) were included. Of the included patients, 86/114 (75.4%) were female. Patients in the 2012-2016 had a median age of 55 compared to 63 in the 2017-2019 group (P=0.02). Otherwise, there was no significant difference in demographic data including time in hospital, treatment option utilized, or aneurysm characteristics. Maximal daily headache score ranged from 6 to 8 for 2012-2016 and 5 to 8 for 2017-2019 cohorts. Average oral morphine equivalents (in mg) administered during hospitalization were similar between groups (2012-2016: 251±345 95% CI [178,323]; 2017-2019: 207±237 95% CI [119,295]; P=0.319). When prescribed, doses of opioids provided at discharge were less in the more recent group (2012-2016: 84.4±78.9 95% CI [57.5, 111]; 2017-2019: 38.1±20.2 95% CI [33.7, 42.5]; P=0.004) CONCLUSION: Despite recognition of important drawbacks of opioid use for headache control, and efforts to reduce opioid use during hospitalization, we found that utilization during hospitalization for SAH did not decrease over time. Maximal headache scores remained similar in the studied time periods, indicative of insufficient pain relief. This points out a pressing need to further investigate alternative opioid and narcotic sparing strategies for patients with SAH.

Augmentation of osseous phenotypes in vivo with a synthetic peptide.

The synthetic peptide B2A2-K-NS augmented the in vitro expression of osseous phenotypes when cells were stimulated with BMP-2, an osteoinductive growth factor. B2A2-K-NS significantly enhanced the effects of BMP-2-induced alkaline phosphatase activity and mineralization. In the absence of BMP-2, B2A2-K-NS did not have an effect on these endpoints. Based on these observations, in vivo studies were conducted to evaluate if B2A2-K-NS could augment osseous phenotypes in an osteoinductive environment in which BMP-2 should be present. In one study, human demineralized bone matrix (DBM) was used to generate an osteoinductive environment and the effects of B2A2-K-NS on ectopic mineralization of subcutaneous implants evaluated. In the second study, a noncritical sized defect in rabbit ulnas with inherent reparative capacity was used as the osteoinductive environment and was treated with or without B2A2-K-NS. In the DBM studies, B2A2-K-NS augmented mineralization as determined using a combination of radiographic analysis and von Kossa staining at 4 weeks postimplant. In the rabbit ulna model, B2A2-K-NS significantly increased the radiographic bone density in the defects compared to carrier-only or no-treatment controls after 6 weeks. Histological staining confirmed that B2A2-K-NS generated a pronounced bone repair response. The results are consistent with the hypothesis that B2A2-K-NS augments osseous phenotypes in an osteoinductive environment, and suggests that B2A2-K-NS may have clinical utility.

Novel formulation of fibroblast growth factor-2 in a hyaluronan gel accelerates fracture healing in nonhuman primates.

Recent advances in understanding the biology of fracture healing and the availability of specific macromolecules has resulted in the development of novel treatments for injuries to bone. Fibroblast growth factor-2 or basic fibroblast growth factor (4 mg/ml), a potent mitogen, and hyaluronan (20 mg/ml), an extracellular matrix component, were combined into a viscous gel formulation intended for direct, percutaneous injection into fresh fractures. In an experimental primate fracture model, a bilateral 1-mm-gap osteotomy was surgically created in the fibulae of baboons. A single direct administration of this hyaluronan/fibroblast growth factor-2 formulation to the defect site significantly promoted local fracture healing as evidenced by increased callus formation and mechanical strength. Radiographic analysis showed that the callus area was statistically significantly larger at the treated sites than at the untreated sites. Specimens treated with 0.1, 0.25, and 0.75 ml hyaluronan/fibroblast growth factor-2 demonstrated a 48, 50, and 34% greater average load at failure and an 82, 104, and 66% greater energy to failure than the untreated controls, respectively. By histologic analysis, the callus size, periosteal reaction, vascularity, and cellularity were consistently more pronounced in the treated osteotomies than in the untreated controls. These results suggest that hyaluronan/fibroblast growth factor-2 may provide a significant advance in the treatment of fractures.

Periodontitis in the baboon: a potential model for human disease.

Advances in periodontics with respect to disease activity, microbiology and immunology have demonstrated the multifactorial nature of periodontal diseases. This serves to underscore the need for an ideal animal model for periodontal research. Non-human primates are most similar to man in comparison to other animal models. The baboon is an Old World monkey that has infrequently been used in periodontal research. Periodontal exams were accomplished on 116 baboons (Papio anubis, P. cynocephalus) ages 5 to 30 years with one baboon year being roughly equivalent to 3 to 4 human years. The study population consisted of 29 males and 87 females. Clinical parameters including probing depth, attachment level, mobility, plaque index and gingival index were collected. Radiographs were taken on 25 animals and correlated to clinical findings. Results showed a significant increase in mean probing depth and mean attachment level with age (p = 0.0001). Disease prevalence and severity were not significantly different between genders. Mobility was uncommon; however, the prevalence and severity of furcation involvement increased with age. Radiographs suggested horizontal and isolated vertical bone loss. Plaque and gingival indices were at sustained high levels for all age groups and showed a statistically significant increase with age. Some baboons were found to develop a naturally-occurring periodontitis that increased in severity with age. This primate may be a suitable model for studies in human periodontal disease.

Diagnostic tools and biologic markers: animal models in the study of osteoporosis and oral bone loss.

Recent data have suggested that there may be a relationship between osteoporosis and oral bone loss. Both diseases are major public health problems of enormous magnitude, but their relationship is poorly understood. This is due to their complex pathogenesis and the fact that coexisting periodontal disease, loss of the dentition, site-specific variability in anatomy and bone density, as well as aging and many other factors complicate the development and progression of bone loss relative to each. The focus of this article is to review the characteristics of animals that are suited for studies of the relationship of osteoporosis and oral bone loss to better understand their relationship.

Osseous implant for studies of biomaterials using an in vivo electrochemical transducer.

The in vitro and in vivo electrochemical behavior of commercially pure titanium (cp Ti) was characterized using a specialized osseous implant in conjunction with electrochemical impedance spectroscopy (EIS) measurement techniques. Studies performed in vitro were used to verify the operation of the transducer and develop methods of deconvoluting EIS data. This method was subsequently used to describe an electrochemical equivalent circuit model of the surface oxide and electrical double-layer capacitance of cp Ti in the endogenous electrolyte found in the medullary compartment of a baboon tibia. Kinetic profiles of the double-layer capacitance and the polarization resistance were constructed from multiple in vitro and in vivo EIS measurements performed over 60 min at 0 V (reference Ag/AgCI) conditioning potential. The profiles demonstrated that the growth of surface oxides was biphasic, with rapid decrease in the double-layer capacitance occurring within 20 min and reaching steady-state conditions at approximately 40 min. These data suggested that a passive, stable biofilm formed on the cp Ti surface in vivo and in vitro.

Experience with osseous implants for bone and biomaterials research.

A Cancellous Access Port (CAP) osseous implant for repeated sampling of cancellous tissue was developed and tested for experimental studies of bone, marrow, and materials biocompatibility. The CAP and associated methods were shown in a series of studies to allow the repeated biopsy of unstrained cancellous tissue with little morbidity and no mortality when used in baboons, rhesus, sheep, and horses. CAP infusion, material testing, and biopsy core assemblies were developed and tested for the administration and assessment of the effects of pharmaceuticals and biologics; the placement and retrieval of a biomaterial with the surrounding tissue; and studies of cancellous bone healing and remodeling.

An intraosseous device for studies of bone-healing. The effect of transforming growth-factor beta.

A novel implantable device, the analytic bone implant, was used in order to establish a model for studies of bone-healing and the evaluation of factors that augment the process, such as transforming growth-factor beta (TGF-beta). This device was implanted into the tibiae of four baboons. After healing, bone was removed from the center chamber. Recombinant human TGF beta-1 was then delivered to the core of the device. After twenty-two days of healing, the device was disassembled and the newly formed bone was removed from the core of the implant for histomorphometric analysis. An analysis of the bone revealed a substantial effect of TGF-beta on osteoblastic activity and proliferation compared with that seen in control and placebo groups. However, despite increased osteoblastic activity, trabecular bone volumes at twenty-two days were equivalent among the groups. The number of osteoclasts and the erosion of the surface were also increased, although not significantly so. Substantial endochondral formation of bone was seen in the supraperiosteal tissues directly over the implants that contained TGF-beta but not over the implants in the control and placebo groups. These data demonstrate the utility of this bone-implant model for studies of bone-healing with minimally invasive methods. In addition, use of the device provided the first in vivo data on the effects of TGF-beta at an intermediate (twenty-two-day) time-point in the healing process in a non-human primate.