Pain, Motivation, Migraine, and the Microbiome: New Frontiers for Opioid Systems and Disease.

For decades the broad role of opioids in addiction, neuropsychiatric disorders, and pain states has been somewhat well established. However, in recent years, with the rise of technological advances, not only is the existing dogma being challenged, but we are identifying new disease areas in which opioids play a critical role. This review highlights four new areas of exploration in the opioid field. The most recent addition to the opioid family, the nociceptin receptor system, shows promise as the missing link in understanding the neurocircuitry of motivation. It is well known that activation of the kappa opioid receptor system modulates negative affect and dysphoria, but recent studies now implicate the kappa opioid system in the modulation of negative affect associated with pain. Opioids are critical in pain management; however, the often-forgotten delta opioid receptor system has been identified as a novel therapeutic target for headache disorders and migraine. Lastly, changes to the gut microbiome have been shown to directly contribute to many of the symptoms of chronic opioid use and opioid related behaviors. This review summarizes the findings from each of these areas with an emphasis on identifying new therapeutic targets. SIGNIFICANCE STATEMENT: The focus of this minireview is to highlight new disease areas or new aspects of disease in which opioids have been implicated; this includes pain, motivation, migraine, and the microbiome. In some cases, this has resulted in the pursuit of a novel therapeutic target and resultant clinical trial. We believe this is very timely and will be a refreshing take on reading about opioids and disease.

Opioid use potentiates the virulence of hospital-acquired infection, increases systemic bacterial dissemination and exacerbates gut dysbiosis in a murine model of Citrobacter rodentium infection.

Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It was recently demonstrated that morphine treatment results in a significant disruption in gut barrier function, leading to an increased translocation of gut commensal bacteria. Further studies have indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences that are associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital-acquired bacterial infection. Citrobacter rodentium is an ideal murine model of human infections with enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC). In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital-acquired bacterial infection. Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) an increase in the expression of the virulence factors of C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of the C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and an increased risk of infections, suggesting that the overprescription of opioids may increase the susceptibility to hospital-acquired infection.

Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome.

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms, and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance, and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that an n-3-PUFA-enriched diet ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and n-3 PUFA supplementation. We demonstrate that the withdrawal of opioids led to a significant depletion in specific microbiota genera, whereas n-3 PUFA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that n-3 PUFA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in n-3 PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

Addiction Medicine Consultations Reduce Readmission Rates for Patients With Serious Infections From Opioid Use Disorder.

The opioid epidemic has increased hospital admissions for serious infections related to opioid abuse. Our findings demonstrate that addiction medicine consultation is associated with increased treatment for opioid use disorder (OUD), greater likelihood of completing antimicrobial therapy, and reduced readmission rates among patients with OUD and serious infections requiring hospitalization.

Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease.

OBJECTIVE: The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health. METHODS: A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior. RESULTS: The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04). CONCLUSIONS: The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin.

Pulmonary and latent tuberculosis screening in opiate drug users: an essential and neglected approach for harm-reduction facilities.

OBJECTIVES: Opiates drug users are at much higher risk of developing tuberculosis (TB) infection than general population. We conducted this study to determine the susceptibility for pulmonary and latent TB infection in opiates drug users. METHODS: In this cross-sectional study, all opiates drug users referred to drop-in centers, methadone maintenance clinics, and harm-reduction facilities affiliated with Shiraz University of Medical Sciences in southern Iran were screened for pulmonary and latent TB infection. RESULTS: The participation rate of opiate drug users was 87.66% (263 of 300). Mean age was 37.37 ± 8.33 (range, 20-65) years. Two hundred twenty-six (85.93%) were male and 197 (74.90%) were injection drug users (IDUs). One hundred sixty-three (61.97%) had TB-related symptoms. Culture for TB was positive in 3 patients (1.14%) (2 non-IDUs and 1 IDU). Two patients (0.76%) showed acid-fast bacilli in the direct sputum smear. Eighty-five of 244 patients (34.83%) had a 5- to 10-mm induration in the skin TB test. Twenty-nine of 223 patients (13%) had abnormal findings from chest x-ray films. CONCLUSIONS: The prevalence of smear-positive pulmonary TB in opiate drug users is more than 100 times in the general population in Iran. Therefore, active and appropriate screening to detect pulmonary TB infection should be integrated into routine activities at all harm-reduction facilities for drug users, irrespective of their route of drug use or human immunodeficiency virus status, in this country.

Effect of opium smoking cessation on the nasopharyngeal microbial flora.

OBJECTIVE: To determine the effect of opium smoking cessation on the frequency and type of microorganisms in the nasopharynx of opium smokers. METHODS: This cross-sectional study was performed in the Psychiatry, and Ear, Nose, and Throat Departments, Moradi Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran from June to November 2008. Nasopharyngeal cultures were taken from 50 opium smokers before, and 2-3 months after cessation of opium smoking. Potential pathogens were identified. Patients were not advised to change their number of cigarettes, and we used methadone for the substitution of opium. RESULTS: Eight potential pathogens were isolated from nasopharyngeal cultures obtained from 43 individuals before opium smoking cessation, and 4 were recovered from 33 individuals after cessation (p=0.03). Streptococcus pneumoniae, Staphylococcus saprophyticus, Streptococcus alpha hemolytic, and Staphylococcus aureus were not found in the second culture. The most sensitivity to antibiotics was for ceftriaxone (84%), ciprofloxacin (74%), and cloxacillin (72%), and the most resistance for amoxicillin (26%) and the least resistance for chloramphenicol. CONCLUSION: Some potential pathogens decrease or are even absent after opium cessation. Opium smoking affects the nasopharyngeal flora.

Carriage of Staphylococcus aureus among injection drug users: lower prevalence in an injection heroin maintenance program than in an oral methadone program.

OBJECTIVES: To compare the prevalence of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) carriage among injection drug users (IDUs) treated in an injection heroin maintenance program with that among IDUs treated in an oral methadone program, and to determine predictors of S. aureus carriage. DESIGN: Survey. SETTING: Two opiate maintenance programs at a psychiatric university clinic. PARTICIPANTS: A volunteer sample consisting of 94 (74%) of 127 IDUs treated in an injection opiate maintenance program with at least twice daily injections of heroin, and 70 (56%) of 125 IDUs treated in an oral methadone program. RESULTS: Addicts treated in the intravenous heroin substitution program had a significantly lower overall rate of S. aureus carriage (37 of 94 [39.4%] vs 42 of 70 [60%]; P = .009) and a significantly lower rate of nasal carriage (21 of 94 [22.3%] vs 30 of 70 [42.9%]; P = .005) than did addicts treated in the oral methadone program. Being treated in the oral methadone program was the only independent predictor of S. aureus carriage (odds ratio, 2.27; 95% confidence interval, 1.19-4.31; P = .012). All S. aureus isolates were susceptible to oxacillin. CONCLUSIONS: The regular use of needles under aseptic conditions did not increase the rate of S. aureus carriage among IDUs. Further studies are necessary to investigate whether the lower rate of S. aureus carriage among IDUs treated with intravenous heroin leads to a lower incidence of S. aureus infections in these patients.

Opiates and infection.

This review on the effects of opiate use on infectious diseases discusses the complete spectrum of infections in the opiate user, including those of the lung, the GI tract, the skin, the skeletal system, and the CNS. There is both increased prevalence and increased severity of bacterial and viral infections in injection drug users with the outcome of increased morbidity and mortality. The experimental administration of opiates has lead to a greater understanding of the effects on susceptibility to and progression of infectious diseases. Animal models of opiate dependence and infection are reviewed with specific attention to cases in which the opiate-mediated effects are harmful and in which cases they are beneficial.

Soft tissue infections in parenteral drug abusers.

Thirty-four parenteral drug abusers admitted with soft tissue infections underwent bacteriologic and immunologic evaluation. Staphylococcus aureus and beta hemolytic streptococci were the most common organisms recovered. Enteric gram negative aerobes and oral flora were common and enteric anaerobes rare. Absolute lymphopenia and elevations in the IgA, IgG and IgM fractions of the immunoglobulins were common as were false positive VDRL examinations. Cutaneous anergy was found in 83% of the group and 70% of a simultaneously noninfected addict group. Staphylococcal carriage was frequent. Because of variation in the flora between this and other reported groups, ongoing bacteriologic surveillance could be a useful guide to initial antibiotic therapy. Differences in the pattern of immune reaction in this group when compared to different addict groups suggest a difference in antigenic stimulation, possibly as a result of differences in bacteriologic exposure.