Development of opioid analgesic tolerance in rat to extended-release buprenorphine formulated for laboratory subjects.

Buprenorphine in an extended-release formulation intended for use in laboratory subjects is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine may persist in serum once extended-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of extended-release buprenorphine intended for use in laboratory subjects in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg extended-release buprenorphine, analgesic efficacy did not persist for the expected 72 hours. No changes were observed in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to extended-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or extended-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1-3 mg/kg). Rats previously given extended-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in male rats after exposure to the extended-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.

Real-world impact of brain metastases on healthcare utilization and costs in patients with non-small cell lung cancer treated with EGFR-TKIs in the US.

BACKGROUND: Non-small cell lung cancer (NSCLC) with brain metastases (BM) is difficult to treat and associated with poor survival. This study assessed the impact of BM on healthcare-related utilization and costs (HRUC) among patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Adults newly-diagnosed with metastatic NSCLC, initiating first-/second-generation EGFR-TKI treatment, with BM or no BM (NBM), were identified retrospectively from IBM MarketScan healthcare claims databases (2013-2017). HRUC were measured during the variable-length follow-up period. Generalized linear models assessed the impact of BM on total healthcare costs, standardized to 2017 US$. RESULTS: Overall, 222 BM and 280 NBM patients were included, with a mean duration of follow-up of 14 months. Adjusted NSCLC-related and all-cause costs over average follow-up were 1.2 times higher among BM patients (Δ$5,640 and Δ$6,366, respectively; p <0.05); differences were driven primarily by radiation treatment and radiology. More than two times more BM than NBM patients received NSCLC-related radiation treatment, in both inpatient (15.3% vs 6.8%; p <0.05) and outpatient settings (87.8% vs 37.5%; p <0.05). Per-patient per-month (PPPM) radiation costs were also higher among BM patients, both inpatient ($796 vs $464, p =0.172) and outpatient ($2,443 vs $747, p <0.05). All-cause PPPM radiology visits (2.0 vs 1.3) and associated costs ($3,824 vs $1,621) were higher among BM patients (both p <0.05). CONCLUSION: NSCLC-related HRUC, especially those attributable to radiation treatment, were higher among patients with BM. Future research should compare the potential for CNS-active EGFR-TKIs vs first-/second-generation EGFR-TKIs combined with radiotherapy to reduce HRUC.

Sustained-release buprenorphine induces acute opioid tolerance in the mouse.

Sustained-release buprenorphine is widely used in mice with the intention of providing long-lasting analgesia. Statements about duration of therapeutic efficacy are based on persistence of serum buprenorphine levels over a minimum threshold, but behavioral data demonstrating sustained efficacy is not established. Additionally, chronic opioid exposure can induce tolerance and/or hyperalgesia; mice receiving sustained-release buprenorphine have not been evaluated for these effects. This study assessed clinical efficacy and duration of sustained-release buprenorphine in inflammatory, post-operative, and cancer pain; and screened for centrally-mediated opioid-induced hyperalgesia as well as opioid tolerance. At 1-2 mg/kg sustained-release buprenorphine, statistically significant analgesic efficacy occurred only at time points up to 2 h. These animals showed no changes in von Frey thresholds on the contralateral side, i.e. no centrally-mediated opioid hyperalgesia. To establish whether acute onset opioid tolerance resulted from a single sustained-release buprenorphine administration, we used the tail flick assay, exposing mice to sustained-release buprenorphine or saline on Day 1 and buprenorphine on Day 2. We measured duration and efficacy of 1 mg/kg buprenorphine after 1 mg/kg sustained-release buprenorphine, and also quantified a dose-response curve of buprenorphine (0.1-3 mg/kg) after 2 mg/kg sustained-release buprenorphine. Compared to control animals, mice previously exposed to sustained-release buprenorphine showed diminished analgesic response to buprenorphine; the resultant dose-response curve showed decreased efficacy. Pretreatment with naloxone, an opioid receptor antagonist, blocked sustained-release buprenorphine analgesic action. The short duration of antinociception following administration of sustained-release buprenorphine in mice is caused by the rapid development of tolerance.

The Study of Pain in Rats and Mice.

Pain is a clinical syndrome arising from a variety of etiologies in a heterogeneous population, which makes successfully treating the individual patient difficult. Organizations and governments recognize the need for tailored and specific therapies, which drives pain research. This review summarizes the different types of pain assessments currently being used and the various rodent models that have been developed to recapitulate the human pain condition.

Seroprevalence of Brucella canis antibodies in dogs entering a Minnesota humane society, Minnesota, 2016-2017.

BACKGROUND: Canine brucellosis, caused by the bacterium Brucella canis, is a zoonotic and largely reproductive disease of dogs. The disease is a recognized problem in canine breeding populations, and the risk to individuals assisting with birthing is well described. Prior to 2015, all cases of canine brucellosis reported to the Minnesota Board of Animal Health were in dogs used for breeding. In 2015, canine brucellosis was identified in eight Minnesota rescue dogs, all originating from specific geographic areas in South Dakota. Our objective was to measure the seroprevalence of B. canis in stray and previously owned dogs entering a large Minnesota animal rescue organization to determine if our observations represented a localized or generalized disease issue among rescue dogs. METHODS: A stratified random sample of stray and previously owned dogs entering the largest Minnesota animal rescue organization between November 1, 2016 and November 7, 2017, was tested for B. canis antibodies by the 2-Mercaptoethanol Rapid Slide Agglutination Test (2ME-RSAT) (Zoetis d-TEC® CB kit). Sample sizes for each strata were calculated using previously published seroprevalence estimates. Blood from selected dogs was collected, serum harvested, and transported to the Minnesota Veterinary Diagnostic Laboratory for testing. Positive samples in the 2ME-RSAT were shipped to Cornell University for confirmation by Agarose Gel Immunodiffusion (AGID) testing. Demographics, state and setting of origin, and health status were collected on study-dogs. RESULTS: Of the 10,654 dogs accepted by AHS during the study period, 943 (8.9%) were selected for testing. Most study dogs arrived from Oklahoma (28%), Alabama (18%), and Minnesota (12%). The median age of study dogs was 1.5 years; 303 (32%) were intact males and 294 (31%) were intact females. Most study dogs were strays (n = 716, 76%). Of the total, 22 (3.1%) stray and eight (3.5%) owner-surrendered dogs were presumptively positive by RSAT; one (0.11%) of the stray dogs was positive by 2ME-RSAT and confirmed by AGID. The positive dog was a healthy-appearing 1 year-old neutered male beagle from Texas. CONCLUSIONS: The seroprevalence of canine brucellosis in dogs entering Minnesota for adoption from multiple states was low. Never-the-less, care must to be taken to consider all potential risks and outcomes of interstate and international dog trade, including the spread of infectious diseases such as canine brucellosis.

Defining and Managing Pain in Stroke and Traumatic Brain Injury Research.

Neurologic conditions such as stroke and traumatic brain injury are challenging conditions to study in humans. Animal models are necessary to uncover disease processes and develop novel therapies. When attempting to model these or other neurologic diseases, the accompanying anesthesia and analgesia create variables that are not part of the onset of the clinical disease in the human population but are critical components of the postinjury care both in humans and animals. To maximize model validity, researchers must consider whether the disease process or a novel therapy is being studied. Damage to the neurons of the brain or the spinal cord is not painful at the neural tissue itself, but alterations to nociceptive signaling along the pain pathway can induce chronic pain. In addition, trauma or surgery leading to the event is associated with damage to peripheral tissue. Inflammation is inextricably associated with tissue injury. Inflammation is known to evoke nociception in the periphery and drive long-term changes to neurons in the CNS. Analgesics and anesthetics alter these responses yet are required as part of humane animal care. Careful planning for effective drug administration consistent with the standard of care for humans and equivalent animal care is required.

Changes in women's feelings about their romantic relationships across the ovulatory cycle.

According to the dual mating hypothesis, women possess two overlapping suites of mate-choice mechanisms: one leading to preferences for sexually desirable men who have high-fitness genes and one leading to preferences for men who are able to invest in a woman and her children. Evidence increasingly demonstrates that women's preference for sexual desirability (but not investment attractiveness) increases when women are most fertile within the ovulatory cycle. Little is known, however, about the implications of these preference shifts for women's relationships with their long-term partners. Using luteinizing hormone tests to verify ovulation, across two studies (Samples 1 and 2), we found that women whose partners were relatively low in sexual desirability felt less close to their partner (Samples 1 and 2) and were more critical of their partner's faults (Sample 2) on high-fertility days of the cycle just prior to ovulation compared with low-fertility days of the cycle. Women whose partners were relatively high in sexual desirability felt closer to their partner (Sample 1) and more satisfied with their relationship (Sample 2) on high- than low-fertility days of the cycle. There were no such shifts in women's commitment to their relationship. Therefore, partner sexual desirability predicts women's high-fertility assessments of relationship quality but not their intentions to stay in their relationship, consistent with the dual mating hypothesis. These findings suggest that variations across the ovulation cycle in women's reproductive hormones play an important role in relationship dynamics.