Self-Reported Marijuana Use Is Associated with Increased Use of Prescription Opioids Following Traumatic Musculoskeletal Injury.

BACKGROUND: Cannabinoids are among the psychoactive substances considered as alternatives to opioids for the alleviation of acute pain. We examined whether self-reported marijuana use was associated with decreased use of prescription opioids following traumatic musculoskeletal injury. METHODS: Our analysis included 500 patients with a musculoskeletal injury who completed a survey about their marijuana use and were categorized as (1) never a user, (2) a prior user (but not during recovery), or (3) a user during recovery. Patients who used marijuana during recovery indicated whether marijuana helped their pain or reduced opioid use. Prescription opioid use was measured as (1) persistent opioid use, (2) total prescribed opioids, and (3) duration of opioid use. Persistent use was defined as the receipt of at least 1 opioid prescription within 90 days of injury and at least 1 additional prescription between 90 and 180 days. Total prescribed opioids were calculated as the total morphine milligram equivalents (MME) prescribed after injury. Duration of use was the interval between the first and last opioid prescription dates. RESULTS: We found that 39.8% of patients reported never having used marijuana, 46.4% reported prior use but not during recovery, and 13.8% reported using marijuana during recovery. The estimated rate of persistent opioid use ranged from 17.6% to 25.9% and was not associated with marijuana use during recovery. Marijuana use during recovery was associated with increases in both total prescribed opioids (regression coefficient = 343 MME; 95% confidence interval [CI] = 87 to 600 MME; p = 0.029) and duration of use (coefficient = 12.5 days; 95% CI = 3.4 to 21.5 days; p = 0.027) compared with no previous use (never users). Among patients who reported that marijuana decreased their opioid use, marijuana use during recovery was associated with increased total prescribed opioids (p = 0.008) and duration of opioid use (p = 0.013) compared with never users. CONCLUSIONS: Our data indicate that self-reported marijuana use during injury recovery was associated with an increased amount and duration of opioid use. This is in contrast to many patients' perception that the use of marijuana reduces their pain and therefore the amount of opioids used. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Patient Perceptions of the Use of Medical Marijuana in the Treatment of Pain After Musculoskeletal Trauma: A Survey of Patients at 2 Trauma Centers in Massachusetts.

OBJECTIVE: To evaluate musculoskeletal trauma patients' beliefs regarding the usefulness of marijuana as a valid medical treatment for postinjury and postoperative pain and anxiety. DESIGN: Prospective survey. SETTING: Two academic Level 1 trauma centers. PATIENTS/PARTICIPANTS: Five hundred patients in an orthopedic outpatient clinic. INTERVENTION: Survey. MAIN OUTCOME MEASUREMENTS: (1) Do patients believe that marijuana can be used as medicine? (2) Do patients believe that marijuana can help treat postinjury pain? (3) Are patients comfortable speaking with their health care providers about medical marijuana? RESULTS: The majority of patients felt that marijuana could be used to treat pain (78%, 390) and anxiety (62%, 309). Most patients (60%, 302) had used marijuana at least once previously, whereas only 14% reported using marijuana after their injury. Of those who used marijuana during their recovery, 90% (63/70) believed that it reduced symptoms of pain, and 81% (57/70) believed that it reduced the amount of opioid pain medication they used. CONCLUSIONS: The majority of patients in this study believed that medical marijuana is a valid treatment and that it does have a role in reducing postinjury and postoperative pain. Those patients who used marijuana during their recovery felt that it alleviated symptoms of pain and reduced their opioid intake. Our results help inform clinicians regarding the perceptions of patients with trauma regarding the usefulness of marijuana in treating pain and support further study into the utility of medical marijuana in this population.

Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome.

Cardiac mitochondrial phospholipid acyl chains regulate respiratory enzymatic activity. In several diseases, the rodent cardiac phospholipidome is extensively rearranged; however, whether specific acyl chains impair respiratory enzyme function is unknown. One unique remodeling event in the myocardium of obese and diabetic rodents is an increase in docosahexaenoic acid (DHA) levels. Here, we first confirmed that cardiac DHA levels are elevated in diabetic humans relative to controls. We then used dietary supplementation of a Western diet with DHA as a tool to promote cardiac acyl chain remodeling and to study its influence on respiratory enzyme function. DHA extensively remodeled the acyl chains of cardiolipin (CL), mono-lyso CL, phosphatidylcholine, and phosphatidylethanolamine. Moreover, DHA lowered enzyme activities of respiratory complexes I, IV, V, and I+III. Mechanistically, the reduction in enzymatic activities were not driven by a dramatic reduction in the abundance of supercomplexes. Instead, replacement of tetralinoleoyl-CL with tetradocosahexaenoyl-CL in biomimetic membranes prevented formation of phospholipid domains that regulate enzyme activity. Tetradocosahexaenoyl-CL inhibited domain organization due to favorable Gibbs free energy of phospholipid mixing. Furthermore, in vitro substitution of tetralinoleoyl-CL with tetradocosahexaenoyl-CL blocked complex-IV binding. Finally, reintroduction of linoleic acid, via fusion of phospholipid vesicles to mitochondria isolated from DHA-fed mice, rescued the major losses in the mitochondrial phospholipidome and complexes I, IV, and V activities. Altogether, our results show that replacing linoleic acid with DHA lowers select cardiac enzyme activities by potentially targeting domain organization and phospholipid-protein binding, which has implications for the ongoing debate about polyunsaturated fatty acids and cardiac health.

Short-term consumption of n-3 PUFAs increases murine IL-5 levels, but IL-5 is not the mechanistic link between n-3 fatty acids and changes in B-cell populations.

N-3 polyunsaturated fatty acids (PUFAs) exert immunomodulatory effects on B cells. We previously demonstrated that n-3 PUFAs enhanced the relative percentage and/or frequency of select B2 cell subsets. The objectives here were to determine if n-3 PUFAs (a) could boost cytokines that target B-cell frequency, (b) enhance the frequency of the B1 population and (c) to identify the mechanism by which n-3 PUFAs modify the proportion of B cells. Administration of n-3 PUFAs as fish oil to C57BL/6 mice enhanced secretion of the Th2 cytokine IL-5 but not IL-9 or IL-13. N-3 PUFAs had no influence on the percentage or frequency of peritoneal B1 or B2 cells. Subsequent experiments with IL-5(-/-) knockout mice showed n-3 PUFAs decreased the percentage of bone marrow B220(lo)IgM(hi) cells and increased the proportion and number of splenic IgM(+)IgD(lo)CD21(lo) cells compared to the control. These results, when compared with our previous findings with wild-type mice, suggested IL-5 had no role in mediating the effect of n-3 PUFAs on B-cell populations. To confirm this conclusion, we assayed IL-5 secretion in a diet-induced obesity model in which n-3 PUFAs enhanced the frequency of select B-cell subsets. N-3 PUFA supplementation as ethyl esters to obesogenic diets did not alter circulating IL-5 levels. Altogether, the data establish that n-3 PUFAs as fish oil can increase circulating IL-5 in lean mice, which has implications for several disease end points, but this increase in IL-5 is not the mechanistic link between n-3 PUFAs and changes in B-cell populations.

Do fish oil omega-3 fatty acids enhance antioxidant capacity and mitochondrial fatty acid oxidation in human atrial myocardium via PPARγ activation?

Abstract Studies in experimental models suggest that n-3 polyunsaturated fatty acids (PUFAs) improve metabolic and anti-inflammatory/antioxidant capacity of the heart, although the mechanisms are unclear and translational evidence is lacking. In this study, patients ingested a moderately high dose of n-3 PUFAs (3.4 g/day eicosapentaenoic (EPA) and doxosahexaenoic acid (DHA) ethyl-esters) for a period of 2-3 weeks before having elective cardiac surgery. Blood was obtained before treatment and at the time of surgery, and myocardial tissue from the right atrium was also dissected during surgery. Blood EPA levels increased and myocardial tissue EPA and DHA levels were significantly higher in n-3 PUFA-treated patients compared with untreated, standard-of-care control patients. Interestingly, n-3 PUFA patients had greater nuclear transactivation of peroxisome proliferator-activated receptor-γ (PPARγ), fatty acid metabolic gene expression, and enhanced mitochondrial respiration supported by palmitoyl-carnitine in the atrial myocardium, despite no difference in mitochondrial content. Myocardial tissue from n-3 PUFA patients also displayed greater expression and activity of key antioxidant/anti-inflammatory enzymes. These findings lead to our hypothesis that PPARγ activation is a mechanism by which fish oil n-3 PUFAs enhance mitochondrial fatty acid oxidation and antioxidant capacity in human atrial myocardium, and that this preoperative therapeutic regimen may be optimal for mitigating oxidative/inflammatory stress associated with cardiac surgery.

n-3 PUFAs enhance the frequency of murine B-cell subsets and restore the impairment of antibody production to a T-independent antigen in obesity.

The role of n-3 polyunsaturated fatty acids (PUFA) on in vivo B-cell immunity is unknown. We first investigated how n-3 PUFAs impacted in vivo B-cell phenotypes and antibody production in the absence and presence of antigen compared with a control diet. Lean mice consuming n-3 PUFAs for 4 weeks displayed increased percentage and frequency of splenic transitional 1 B cells. Upon stimulation with trinitrophenylated-lipopolysaccharide, n-3 PUFAs increased the number of splenic transitional 1/2, follicular, premarginal, and marginal zone B cells. n-3 PUFAs also increased surface, but not circulating, IgM. We next tested the effects of n-3 PUFAs in a model of obesity that is associated with suppressed humoral immunity. An obesogenic diet after ten weeks of feeding, relative to a lean control, had no effect on the frequency of B cells but lowered circulating IgM upon antigen stimulation. Administration of n-3 PUFAs to lean and obese mice increased the percentage and/or frequency of transitional 1 and marginal zone B cells. Furthermore, n-3 PUFAs in lean and obese mice increased circulating IgM relative to controls. Altogether, the data show n-3 PUFAs enhance B cell-mediated immunity in vivo, which has implications for immunocompromised populations, such as the obese.

Dendritic cell activation, phagocytosis and CD69 expression on cognate T cells are suppressed by n-3 long-chain polyunsaturated fatty acids.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are bioactive n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in fish oil that exert immunosuppressive effects. A significant amount of literature shows that n-3 LCPUFAs suppress dendritic cell (DC) function in vitro; however, few studies have determined if the effects are emulated at the animal level. In this study, we first focused on the functional consequences of 5% (weight/weight) fish oil on splenic CD11c(+) DCs. Administration of n-3 LCPUFAs, modelling human pharmacological intake (2% of total kcal from EPA,1·3% from DHA), to C57BL/6 mice for 3 weeks reduced DC surface expression of CD80 by 14% and tumour necrosis factor-α secretion by 29% upon lipopolysaccharide stimulation relative to a control diet. The n-3 LCPUFAs also significantly decreased CD11c(+) surface expression and phagocytosis by 12% compared with the control diet. Antigen presentation studies revealed a 22% decrease in CD69 surface expression on transgenic CD4(+) T lymphocytes activated by DCs from mice fed fish oil. We then determined if the functional changes were mechanistically associated with changes in lipid microdomain clustering or plasma membrane microviscosity with n-3 LCPUFAs, as reported for B and T lymphocytes. Fish oil administration to mice did not influence cholera-toxin induced lipid microdomain clustering or microviscosity, even though EPA and DHA levels were significantly elevated relative to the control diet. Overall, our data show that n-3 LCPUFAs exert immunosuppressive effects on DCs, validating in vitro studies. The results also show that DC microdomain clustering and microviscosity were not changed by the n-3 LCPUFA intervention used in this study.

DHA-enriched fish oil targets B cell lipid microdomains and enhances ex vivo and in vivo B cell function.

DHA is a n-3 LCPUFA in fish oil that generally suppresses T lymphocyte function. However, the effect of fish oil on B cell function remains relatively understudied. Given the important role of B cells in gut immunity and increasing human fish oil supplementation, we sought to determine whether DFO leads to enhanced B cell activation in the SMAD-/- colitis-prone mouse model, similar to that observed with C57BL/6 mice. This study tested the hypothesis that DHA from fish oil is incorporated into the B cell membrane to alter lipid microdomain clustering and enhance B cell function. Purified, splenic B cells from DFO-fed mice displayed increased DHA levels and diminished GM1 microdomain clustering. DFO enhanced LPS-induced B cell secretion of IL-6 and TNF-α and increased CD40 expression ex vivo compared with CON. Despite increased MHCII expression in the unstimulated ex vivo B cells from DFO-fed mice, we observed no difference in ex vivo OVA-FITC uptake in B cells from DFO or CON mice. In vivo, DFO increased lymphoid tissue B cell populations and surface markers of activation compared with CON. Finally, we investigated whether these ex vivo and in vivo observations were consistent with systemic changes. Indeed, DFO-fed mice had significantly higher plasma IL-5, IL-13, and IL-9 (Th2-biasing cytokines) and cecal IgA compared with CON. These results support the hypothesis and an emerging concept that fish oil enhances B cell function in vivo.

High dose of an n-3 polyunsaturated fatty acid diet lowers activity of C57BL/6 mice.

n-3 Polyunsaturated fatty acids (PUFA) are increasingly consumed as food additives and supplements; however, the side effects of these fatty acids, especially at high doses, remain unclear. We previously discovered a high fat n-3 PUFA diet made of fish/flaxseed oils promoted significant weight gain in C57BL/6 mice, relative to a control, without changes in food consumption. Therefore, here we tested the effects of feeding mice high fat (HF) and low fat (LF) n-3 PUFA diets, relative to a purified control diet (CD), on locomotor activity using metabolic cages. Relative to CD, the HF n-3 PUFA diet, but not the LF n-3 PUFA diet, dramatically reduced ambulatory, rearing, and running wheel activities. Furthermore, the HF n-3 PUFA diet lowered the respiratory exchange ratio. The data suggest mixed fish/flaxseed oil diets at high doses could exert some negative side effects and likely have limited therapeutic applications.

The effectiveness of the controlled release of gentamicin from polyelectrolyte multilayers in the treatment of Staphylococcus aureus infection in a rabbit bone model.

While the infection rate of orthopedic implants is low, the required treatment, which can involve six weeks of antibiotic therapy and two additional surgical operations, is life threatening and expensive, and thus motivates the development of a one-stage re-implantation procedure. Polyelectrolyte multilayers incorporating gentamicin were fabricated using the layer-by-layer deposition process for use as a device coating to address an existing bone infection in a direct implant exchange operation. The films eluted about 70% of their payload in vitro during the first three days and subsequently continued to release drug for more than four additional weeks, reaching a total average release of over 550 microg/cm(2). The coatings were demonstrated to be bactericidal against Staphylococcus aureus, and degradation products were generally nontoxic towards MC3T3-E1 murine preosteoblasts. Film-coated titanium implants were compared to uncoated implants in an in vivo S. aureus bone infection model. After a direct exchange procedure, the antimicrobial-coated devices yielded bone homogenates with a significantly lower degree of infection than uncoated devices at both day four (p < 0.004) and day seven (p < 0.03). This study has demonstrated that a self-assembled ultrathin film coating is capable of effectively treating an experimental bone infection in vivo and lays the foundation for development of a multi-therapeutic film for optimized, synergistic treatment of pain, infection, and osteomyelitis.