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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. However, real-world studies in chronic non-cancer pain CNCP remain scarce. Our aim was to compare effectiveness and security in daily pain practice, together with the influence of pharmacogenetic markers. CNCP real-world patients achieved higher pain relief than other traditional opioids with a better tolerability for TAP. In last decades, prescription opioids began to be used for chronic non-cancer pain CNCP outside the context of palliative medicine 1 , 2. Since then, there has been an increase in opioid long-term use for conditions that are beyond the evidence base 3 , 4. New, recently marketed opioid with potentially improved tolerability have opened a more optimistic door. Another new opioid is tapentadol TAP , that has a dual mode of action. The main question is whether this better profile is maintained or changed in real-world pain practice with polymedicated and elderly regular pain patients. Given this scenario, precision medicine could provide data to understand such variability. There are few validated studies that ultimately call for pharmacogenetic testing to be conducted when initiating opioid therapy in pain management 19 , 20 , 21 , 22 , Results have indicated that many favourable analgesic effects may depend on increased OPRM density 24 , 25 and on higher dopamine concentrations in the prefrontal cortex Chronic pain was mostly due to lumbago nonspecific, associated with radiculopathy, spinal stenosis, or another specific spinal cause , followed by knee pain. Nearly half of them had mixed neuropathic-nociceptive symptoms. A summary of the characteristics of the subjects included in the study is presented in Table 1. A significant positive correlation was evidenced between pain relief and QoL in cases with a negative correlation to pain intensity in all groups. A summary of the prescribed analgesic drugs is presented in Table 2 and Fig. In contrast, the controls required higher tramadol use than cases. On the other hand, the rates of coadjuvant medication use differed between groups. Gabapentin cases vs. Hence, they were not included in the final analysis due to their low prescription rate. The percentage of patients showing some AE is displayed in Fig. In this case, no statistically significant influence was found over these variables. Any genetic variant analysed influence on incidence of AEs in cases. These results provide clear directions in terms of clinical practice. Firstly, as expected, control group reported a higher frequency of severe pain 29 that together with the QoL, could be predictive for a higher pain relief Thus, our results would hold for similar pain patients that routinary attends PUs. Secondly, data evidenced that OXN yielded higher pain relief 32 , 33 but with a higher prevalence of side-effects including constipation rates , drug change requirements due to pain or hospital frequentations due to other causes. Our results suggest that TAP could provide better clinical outcomes at lower costs due the lower opioid requirements and incidence of AEs Here, the TAP more frequent weight change compared to other groups should be deeper analysed. Prior studies have identified an association between obesity and prescription opioid use in the US. However, the pain conditions that are factors in this association remain unestablished 38 and this. Additional larger studies are needed to evaluate these results and, also, whether genotyping COMT , alone or in combination with OPRM1, could be potentially translated to pain practice Our data showed a mild COMT genetic influence on some side-effects, such as erythema and vomiting, especially in females. This can be mediated by dopamine, which is an important neurotransmitter in the postrema area and vomiting centre, when it is used together with catecholamines that can modulate inflammatory processes In addition, the remarkably female predominance in this data merits further attention. Mostly of our patients were elderly women, as was previously highlighted in our pain population Literature data strongly suggest that men and women differ in their pain responses, potentially due to differences in modulation of the endogenous opioid system 43 and sex hormones 44 , which could, in turn, have differential pharmacogenetic impacts 45 , Awareness about this sex influence should be emphasized in order to improve pain management. Our data present some limitations. First, the lack of randomization is problematic and raises questions about bias. This should be addressed in future studies. This potentially clouds an understanding of what types of non-opioid analgesics as duloxetine or pregabalin could be appropriate for use. This could have introduced a bias influenced by several other variables, such as sociodemographics, that might be more relevant than pain status Second, a convenience sample was assessed based on patients attending the PU. This can affect the population representativeness, especially in genotype variables, and in this way to find significant differences. Thus, AEs could not be always directly attributed to the opioid with the highest prescribed dose. This may limit conclusions related to effectiveness or side-effects. Finally, while a combination of Oxycodone with naloxone may have benefits related to gastrointestinal side effects, potential interactions between these drugs have not been contemplated in this study. All these aspects should be addressed in future studies. Taken together the findings presented here suggest that opioids of the new generation, OXN and TAP, can control pain intensity than traditional opioids used in pain treatment routines. Additionally, COMT genotypes were associated with higher incidence of some opioid side-effects, especially in females. Hence, further studies are warranted to confirm and refine these results on a wider population and finally ascertain the role that pharmacogenetic in terms of improve analgesic tolerability. At the time of the enrolment, all participants received information on the design and purpose of the study and provided their written informed consent, allowing their genetic samples and electronic health records EHRs to be used for the research. All the methods were carried out in accordance with the ethical guidelines established in the Declaration of Helsinki. Although patients under 18 years old, pregnant women, oncologic pain or any psychiatric disorders that could interfere with the proper development of the study were excluded. Furthermore, other chronic pain syndromes of unclear pathophysiology, such as fibromyalgia, and neuropathic pain, such as painful polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain, were not included There was no minimum pain score required for inclusion in the study. First, the researchers reviewed the schedule of PU consultations by patients weekly. Then they pre-screened patients with active OXN or TAP prescriptions and prepared the questionnaires and informed consent forms. For every two cases, one control was included from a concomitant observarional study 12 age and sex-matched patients with the same inclusion criteria yet treated with opioids different from TAP or OXN as fentanyl, morphine or buprenorphine. The population selected as controls included a total of clinical records of patients who routinely attend to PU for treat their CNCP. From this group, a subpopulation of patients was extracted who were being treated with a main opioid excluding OXN, oxycodone without combination or TAP being main analgesic drug adjuvants prescription rate gabapentin, duloxentin , similar to those of the test cases studied. A consecutive sampling method was used in ambulatory patients. Then, interested individuals were attended to by the research staff for signing of the informed consent paperwork and collection of a saliva sample for the pharmacogenetic analysis. Demographic data, pain history, drug use and medical history were recorded from EHRs. Clinical data was reported through validated scales and questionnaires completed as part of a standard clinical routine for assessing pain intensity, pain relief, QoL, and most common AEs in pain management Outcomes were assessments at a single time point where pain intensity or relief and QoL was asked at the present time whilst the cumulative AEs reported since last month. Validated scales and questionnaires were used to evaluate clinical outcomes and were collected every time a patient was included at a single time point. Pain intensity, relief and QoL were measured using the visual analogue scale VAS , consecutively by clinical routine. These AEs consisted of: sleepiness, dizziness, nausea, vomiting, constipation, itchiness, sexual dysfunction, loss of libido, weight change, headache, erythema, dry skin, dry mouth, edema, depression, insomnia, nervousness and loss of appetite. In addition, the percentage of Emergency Department ED visits, hospitalizations, or any drug changes due to pain or other causes were registered when patients were included referred to the last month. Prescription changes included: 1 Change in any drug-dosage. In cases where different opioids were combined, oral MEDD was estimated using available references Approximately 2 ml of saliva was collected in tubes containing 6 ml of PBS. Genomic DNA was isolated using the E. Convenience sampling was considered to be more likely to represent the target population. This entailed selecting participants on the basis of availability until the final sample size was achieved The assumption of normality was validated with the Kolmogorov Smirnov test using the Lilliefors correction method. Categorical data is expressed by percentages, among them the relative frequencies of genotypes and alleles. Comparisons between any two given groups case, controls of data exhibiting parametric distributions was conducted using the independent T-test analysis, and for analyses comparing three groups an ANOVA test was carried out. Analysis of non-parametric data was done using U Mann—Whitney and Kruskal—Wallis tests for comparison between two and three groups, respectively. A multiple linear regression was performed to generate a predictive risk model and to analyse the influence of the following variables over pain relief: age, gender, VAS pain intensity, EQD, MEDD, number of AEs and the use of neuromodulators, anxiolytics, and analgesics. In addition to this, the effect sizes were calculated for all the comparisons. Chi-square test analysis was conducted to compare the distribution of genotypes and alleles between the different groups. The subjects were grouped based on their genetic profiles, whether they were homozygotes or heterozygous, and whether they were carriers or non-carriers of a determinate allele. In cases of significant genetic associations, co-dominant, dominant, recessive, and over-dominant models were calculated. In all cases, multiple testing was adjusted using the Bonferroni correction. Analyses were carried out using the R software package version 4. Dowell, D. CDC guideline for prescribing opioids for chronic pain—United States, MMWR Recommend. Article Google Scholar. Hardt, J. Prevalence of chronic pain in a representative sample in the United States. Pain Med. Article PubMed Google Scholar. Muriel, J. Pharmacogenetics and prediction of adverse events in prescription opioid use disorder patients. Basic Clin. Fernandes, K. High-Dose opioid prescribing and opioid-related hospitalization: A population-based study. Alexander, G. Google Scholar. Pathan, H. Basic opioid pharmacology: An update. Pain 6 , 11—16 Ueberall, M. Pain Res. Kang, J. Opioid withdrawal syndrome after treatment with low-dose extended-release oxycodone and naloxone in a gastric cancer patient with portal vein thrombosis. Pain Symp. Langford, R. Is tapentadol different from classical opioids? A review of the evidence. Pain 10 , — Biondi, D. Opioid Manage. Planelles, B. Gender based differences, pharmacogenetics and adverse events in chronic pain management. Health benefits of an adverse events reporting system for chronic pain patients using long-term opioids. Acta Anaesthesiol. Afilalo, M. Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: A randomized, double-blind, placebo-and active-controlled phase III study. Drug Investig. Abeyaratne, C. Drug Saf. Haeseler, G. BMC Anesthesiol. Baron, R. Pain Pract. Diatchenko, L. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Kieffer, B. Exploring the opioid system by gene knockout. Hoehe, M. Ablin, J. Personalized treatment of pain. Bonica, J. The relation of injury to pain. Pain 7 , — Kambur, O. Catechol-O-methyltransferase and pain. Cheung, C. Chronic opioid therapy for chronic non-cancer pain: A review and comparison of treatment guidelines. Pain Phys. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain , — Melia, U. Interaction between EEG and drug concentration to predict response to noxious stimulation during sedation-analgesia: Effect of the AG genetic polymorphism. IEEE Eng. PubMed Google Scholar. Crist, R. Pharmacogenetics of OPRM1. Mura, E. Harrison, P. Catechol-O-methyltransferase COMT : A gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33 , — Steigerwald, I. Effectiveness and tolerability of tapentadol prolonged release compared with prior opioid therapy for the management of severe, chronic osteoarthritis pain. Tapentadol treatment results in long-term pain relief in patients with chronic low back pain and associates with reduced segmental sensitization. PAIN Rep. Pergolizzi, J. Opioids and the management of chronic severe pain in the elderly: Consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone. Jespersen, A. Is neuropathic pain underdiagnosed in musculoskeletal pain conditions? Finnerup, N. Lancet Neurol. Coluzzi, F. Gatti, A. Effects of opioid rotation in chronic pain patients. Sarzi-Puttini, P. The appropriate treatment of chronic pain. Merchant, S. Budget impact analysis of tapentadol extended release for the treatment of moderate to severe chronic noncancer pain. Stokes, A. Association of obesity with prescription opioids for painful conditions in patients seeking primary care in the US. JAMA Netw. Open 3 , e Aroke, E. Pharmacogenetics of postoperative nausea and vomiting. Perianesthesia Nurs. Margarit, C. OPRM1 gene interaction with sleep in chronic pain patients treated with opioids. Oh, J. Ranque, B. Interne 38 , — Pieretti, S. Gender differences in pain and its relief. Traub, R. Sex differences and hormonal modulation of deep tissue pain. Samulowitz, A. Sharma, N. Gender differences in caregiving among family—Caregivers of people with mental illnesses. World J. Psychiatry 6 , 7 Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Barrachina, J. Global pain state questionnaire: Reliability, validity, and gender gap. Spanish Agency for Medicines and Health Products. Accessed 9 Sept Sino, C. The association between prescription change frequency, chronic disease score and hospital admissions: A case control study. BMC Pharmacol. Rojas, G. Benefit-Risk Methodology Project. European Medicines Agency. Mercadante, S. Opioid switching from and to tapentadol extended release in cancer patients: Conversion ratio with other opioids. Richards, B. Neuromodulators for pain management in rheumatoid arthritis. Cochrane Database Syst. Mathieson, K. Making sense of biostatistics: Types of nonprobability sampling. Best Pract. Download references. We would like to thank Pain Unit Nurses Mrs. You can also search for this author in PubMed Google Scholar. All the authors reviewed and gave the final approval of the following version to be published and are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Correspondence to Ana M. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Reprints and permissions. Sci Rep 12 , Download citation. Received : 09 January Accepted : 20 May Published : 16 June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma. Skip to main content Thank you for visiting nature. Download PDF. Gender based differences, pharmacogenetics and adverse events in chronic pain management Article 20 November Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects Article Open access 01 June Introduction In last decades, prescription opioids began to be used for chronic non-cancer pain CNCP outside the context of palliative medicine 1 , 2. Results Chronic pain was mostly due to lumbago nonspecific, associated with radiculopathy, spinal stenosis, or another specific spinal cause , followed by knee pain. Demographic and clinical outcomes A summary of the characteristics of the subjects included in the study is presented in Table 1. Full size table. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Limitations and strengths Our data present some limitations. Conclusions Taken together the findings presented here suggest that opioids of the new generation, OXN and TAP, can control pain intensity than traditional opioids used in pain treatment routines. Figure 5. References Dowell, D. Article Google Scholar Hardt, J. Google Scholar Pathan, H. Article Google Scholar Langford, R. Article Google Scholar Planelles, B. Article Google Scholar Diatchenko, L. Article Google Scholar Margarit, C. Google Scholar Oh, J. Article Google Scholar Samulowitz, A. Article Google Scholar Sharma, N. Google Scholar European Medicines Agency. Google Scholar Mercadante, S. Google Scholar Download references. View author publications. Ethics declarations Competing interests The authors declare no competing interests. Additional information Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information. Supplementary Table S1. Supplementary Table S2. Supplementary Table S3. About this article. Cite this article Barrachina, J. Copy to clipboard. Publish with us For authors Language editing services Submit manuscript. Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search. Close banner Close. Email address Sign up. Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research.

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