Sex Bias and Genotype Influence on Opioid Safety Profile in Chronic Low Back Pain.

OBJECTIVES: The use of opioids to relieve pain is a challenge because of the high variability in dose requirements and tolerance profiles. Among potential modulators are the individual's genetic background and being female. Our aim was to evaluate sex bias and genotype-related influence on opioid titration safety, in chronic low back pain (CLBP), the most frequent chronic noncancer pain. METHODS: A 3-year prospective study was developed in opioid-naive CLBP patients. Data were self-reported by patients (pain [Visual Analogy Scale], adverse events [AEs], and health care resource utilization) and physicians (analgesic prescription, morphine equivalent daily dose, and suspected adverse drug reactions [ADRs]). Outcomes were analyzed as patients with AEs (case) or without (control) together with patients' sex and genotype. Gene variants in OPRM1 (rs1799971), COMT (rs4680), ABCB1 (rs1045642), UGT2B7 (rs12233719 and rs7438135), KCNJ6 (rs2070995 and rs6517442), and CYP3A5*3 (rs776746) were assessed. The hospital ethics committee approved the study, and statistical analyses were performed with R, v.3.2.4. RESULTS: A total of 179 patients were included (64% female, mean pain intensity 73±16 mm), and 90% of them presented at least 1 AE (median of 3 (1 to 6) AEs/patient) with a rate of 5 AEs: 1 ADR without differences due to sex. However, there is a significant delay in referral of female patients (a mean of 6 years) to the Pain Unit, being significantly 3 to 5 times more likely to present sleep or psychiatric disorders. Meanwhile male individuals showed more sexual and reproductive system disorders. Genotypes influenced skin (COMT, G472A-GG) and gastrointestinal (ABCB1, C3435T-CC) related problems. CONCLUSIONS: Sex bias affects female patients resulting in a CLBP diagnostic delay and a different analgesic safety profile. Moreover, the individual's genetic background might be useful to predict certain AEs in opioid-naive patients under an opioid titration procedure. Addressing sex in necessary to resolve inequalities in health care access.

Genetic Contribution in Low Back Pain: A Prospective Genetic Association Study.

OBJECTIVES: Chronic pain is one of the most common reasons individuals seek medical attention. It is a major issue because of the wide interindividual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low back pain (CLBP) relief after opioid titration, unveiling the impact of pharmacogenetics. METHODS: The study included 231 opioid-naïve patients from the Spine Unit; age 63 ± 14 years, 64% female, body mass index 29 ± 6 kg/m2 , visual analog scale pain intensity score 73 ± 16 mm. Clinical data were collected at baseline, 3 months after opioid titration, and after 2 to 4 years of follow-up concerning pain (intensity and relief), quality of life, disability, comorbidities, and drug prescription (opioid dose, rotations, and adverse events). The genotype influence of OPRM1, COMT, UGT2B7, ABCB1, KCNJ6, and CYP3A5*3A in analgesic response was analyzed by reverse-transcription polymerase chain reaction genotyping. RESULTS: Patients with the COMT G472A-AA genotype (rs4680) and KCNJ6 A1032G-A allele (rs2070995) CLBP responded differently to opioid titration, with higher pain intensity requiring higher dosing. Furthermore, GG- genotypes of A118G (OPRM1, rs1799971) and A854G (UGT2B7, rs776746) influenced the neuropathic component. After opioid titration, CLBP intensity, neuropathic component, low back pain disability, anxiety, and depression significantly decreased, while quality of life improved. CONCLUSION: Single-nucleotide polymorphisms in genes involved in pain transmission and opioid metabolism might predispose to exaggerated sensitivity and differences in the opioid analgesic effect in patients with CLBP. We encourage clinical trials for their clinical application in chronic pain management.

OPRM1 Gene Interaction with Sleep in Chronic Pain Patients Treated with Opioids.

BACKGROUND: The experience of chronic non-cancer pain (CNCP) is one of the most common reasons individuals seek medical attention. Patients with CNCP frequently experience concomitant sleep-related problems. OBJECTIVES: The aim was to evaluate sleep problems in opioid naïve CNCP patients, before and after opioid titration, analyzing the influence of OPRM1 gene variants. STUDY DESIGN: A prospective, cohort, observational study. SETTING: This study was performed at the Pain Unit of the Alicante University General Hospital. METHODS: Pain and Medical Outcomes Study Sleep questionnaire (MOS-Sleep) were assessed at baseline and 3 months after opioid titration in 231 opioid naïve CNCP patients. Sleep data was compared with a matched-control group (n = 64). Morphine equivalent daily doses, adverse events, and drugs prescribed for pain were also registered. OPRM1 polymorphism rs1799971 was analyzed by RT-PCR. Ethics Committee approved the study and results were analyzed by R software. RESULTS: After 3 months of opioid titration, patients with CNCP (63 ± 14 years, 64% female, VAS 74 ± 17 mm) significantly decreased pain intensity, anxiety and depression, and increased quality of life. Sleep problems were significantly more frequent in females (P = 0.002). Age, quality of life, anxiety, and depression all influenced sleep disturbances and problems indices, which were significantly different from the control group. Furthermore, the OPRM1 118-GG genotype was also associated with significantly lower sleep adequacy, and more sleep problems. LIMITATIONS: Total number of subjects studied was relatively small and most patients were on other non-opioid centrally-acting medications. CONCLUSIONS: Opioids decreased CNCP severity, improving patients' psychological areas, and quality of life. However, patients with OPRM1 118-GG genotype indicated an increase in sleep problems and worsening sleep pattern while taking opioids. KEY WORDS: OPRM1, pharmacogenetics, MOS-Sleep, opioids, chronic noncancer pain, sleep related problems, sleep problem index SLP-6 and SLP-9.

ß2­adrenergic receptor functionality and genotype in two different models of chronic inflammatory disease: Liver cirrhosis and osteoarthritis.

The present study was designed to investigate the functional status of ß2 adrenoceptors (ß2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The ß2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte ß2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13±4 mmHg, CHILD 7±2 and MELD 11±4 scores), OA patients (n=30, 84% Kellgren­Lawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 10­9 to 10­4 mM), and ß2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. ß2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the ß2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the ß2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes.

Presencia de bacterias patógenas en las aguas de la desembocadura del Río Surco y la Playa La Chira, Lima, Perú, junio 2009 / Presence of pathogenic bacteria in the estuary of Surco River and La Chira beach, Lima, Peru, June 2009

El estudio de la calidad microbiológica de las aguas marinas que bañan las playas de cualquier ciudad es de vital importancia para conocer los potenciales impactos que tendrá sobre la salud pública de la población que usa las franjas costeras como zonas de esparcimiento. La presencia de numerosas especies bacterianas como coliformes (Escherichia, Kebsiella, Citrobacter-Enterobacter sp.) Enterococci sp, Pseudomonas aeruginosas, Clostridium penfringens, Aeromonas hydrophila, Vibrio parahaemolyticus y Salmonella sp. suelen correlacionar con la presencia de síntomas gastrointestinales (vómitos, diarreas, náuseas o dolor de estómago) en los bañistas y consumidores de productos frescos del mar. Se realizó, con los estudiantes de la Cátedra de Microbiología de Medicina Humana de la Universidad Ricardo Palma (FAMURP), tomas aleatorias estratificadas de la playa la Chira contigua al colector del mismo nombre durante el mes invernal de junio del 2009, las mismas que fueron procesadas en los laboratorios de Microbiología de la FAMURP. Se encontró por el método de número más probable de concentración bacteriana una elevada contaminación bacteriológica en todos los puntos muestreo, pudiéndose aislar numerosas enterobacterias en los procesos de cultivo.

The study of the microbiological quality of sea water in the beaches near any city is of the outmost importance in order to know the potential impact on the health of the population using the coastal areas as playgrounds. The presence of many bacterial species, such as coliforms (Escherichia coli, Klebsiella, Citrobacter-Enterobacter spp.), Enterococci spp, Pseudomonas aeruginosa, Clostridium perfringens, Aeromonas hydrophila, Vibrio parahaemolyticus, and Salmonella spp., tends to correlate with the occurrence of gastrointestinal symptoms (vomiting, diarrhea, nausea or abdominal pain) in bathers as well as in people eating fresh sea products. The study was performed with students from the Microbiology course in Universidad Ricardo Palma Medical School. Random and stratified samples were collected from La Chira beach during June 2009 (winter in Lima). It is worth mentioning that La Chira beach is located next to a water sewage duct that dumps millions of gallons of wasted water directly in the sea. Samples were processed in Microbiology laboratories from the aforementioned university. Using the most probable number method for bacterial concentrations, a very high bacterial load was found in every place sampled, and many Enterobacteriaceae were found in cultures.