Plasma Brain-Derived Neurotrophic Factor and Opioid Therapy: Results of Pilot Cross-Sectional Study

  • Clinical Medicine & Research
  • December 2022,
  • 20
  • (4)
  • 195-
  • 203;
  • DOI: https://doi.org/10.3121/cmr.2022.1731
PDF

Abstract

Objective: The neurotoxic effect of opioid has not been thoroughly described. No studies have been conducted to explain the effect of opioids in chronic non-cancer pain therapy on the neurotrophic factors level. Due to the ability to cross the blood-brain barrier, it seems the determination of serum Brain-derived neurotrophic factor (BDNF) concentration is a reliable presentation of the concentration in the central nervous system. The aim of the study was to explore the changes of plasma BDNF concentration during long-term opioid therapy.

Methods: The study group included 28 patients with chronic low back pain treated with opioid therapy buprenorphine (n=10), tramadol (n=8), oxycodone (n=6), morphine (n=3), fentanyl (n=1). The control group included 11 patients. Measurements of plasma BDNF concentrations were performed, and information about opioid therapy were recorded (age, sex, opioid substance type, daily dose and the duration of opioid therapy). Data were analyzed using nonparametric tests.

Results: The median BDNF level in the study group was significantly lower (2.73 ng/mL) than that in the control group (5.04 ng/mL, P<0.05). BDNF levels did not differ among groups based on the type of opioid substance used, but the lowest median value was observed for tramadol (2.62 ng/mL), and the highest median value was observed for buprenorphine (2.73 ng/mL). The widest minimum-maximum ranges of BDNF for oxycodone were noted, minimum 1.23 ng/mL and maximum 4.57 ng/mL, respectively. BDNF concentrations were correlated with age in the tramadol group and with the duration of opioid therapy in the buprenorphine group.

Conclusion: Chronic opioid therapy for noncancer pain induces specific changes in the BDNF concentration. Tramadol and buprenorphine exerted an important effect on BDNF levels in the examined patients. The BDNF level depends on duration of opioid therapy with buprenorphine, and age in tramadol therapy.

Keywords:

Important limitations of opioid pharmacotherapy are the risk of developing addiction and tolerance and the occurrence of cognitive and behavioral disorders. These processes are crucial for social and professional functioning. The prevalence of opioid-addictive disorder ranges from 2% to 6%, but many authors have suggested it can be as high as 30%, with a global lifetime prevalence rate of 0.22%.1,2 The number of opioid prescriptions has increased worldwide, and the highest morphine equivalents per capita were described in Canada, the United States, and Denmark. Epidemiological data have shown the increasing trend in opioid administration is common in patients with chronic low back pain (LBP) and other noncancer types of pain, and prescriptions have increased from 19% in 1999 to 29% in 2010; 87% of all morphine equivalents were used by patients receiving long-term opioid therapy.3-5 Importantly, opioids are not the first-line therapy, and the administration of opioids is possible only after careful consideration, including an evaluation of risks and adverse events. Long-term therapy requires patient monitoring and dose and analgesic effect control.6-10

Epidemiological data show that 55% of the population over 20 years-of-age experiences chronic pain, most often in the form of headache, joint pain, severe back pain, or cancer-related pain, and 90% of these individuals have an episode of opioid drug use as an element of pharmacotherapy.11 Moreover, other data indicate that 8.5% of patients who have undergone opioid therapy then continue this therapy model for a year, while only 2.1% of NSAID users continue it over the next year.12

The use of opioid drugs to treat chronic pain is a very real issue. The most commonly known adverse reactions associated with the use of opioid drugs are nausea and vomiting, as well as constipation. Recommendations have already been developed for these adverse reactions, and effective methods have been developed to prevent and treat these symptoms.12-16

Experimental studies have described significant pathophysiological pathways underlying the effects of opioid drugs on components of the central and peripheral nervous systems. Long-term opioid therapy induces dysregulation of the immune system and damage neurons with secondary glial cell stimulation and the upregulation of proinflammatory mechanisms. Microglial activation increases neuronal apoptosis and neurotoxicity. Other findings suggest that chronic opioid administration induces neuronal degeneration and decreases neurotrophin expression.2,17-20 The loss of neuronal functions is associated with impaired concentration, learning, memory function, and emotional states. Sustained systemic or spinal opioid administration results in the substantial upregulation of microglial markers, including receptor expression (CD11b, Iba1, and ATP receptors P2X4 and P2X7), protein synthesis (glial fibrillary acidic protein, glial derived proinflammatory cytokines) and the phosphorylation of p38-mitogen-activated protein kinase with deactivation. Proinflammatory cytokines decrease gamma-aminobutyric acid (GABA) receptor expression, increase alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor activity, reduce the levels of glutamate transporter proteins and decrease outward potassium currents, ultimately resulting in neuronal excitability and destruction.11,20-24

Various markers have been used to describe the intensity of neurodegenerative processes. Many authors have noted the high clinical value of C-reactive protein, proinflammatory interleukins (IL-6, -8, -10, -4, and -2) and oxidative stress markers (thiobarbituric acid-reactive substances, superoxide dismutase and catalase activities, total antioxidant capacity and total oxidant capacity). Brain-derived neurotrophic factor (BDNF) is a member of a group of nerve growth factors described for the first time in 1982.25 It plays a pivotal role in the physiology of neuronal cells, including their outgrowth, differentiation, repair and survival. Many studies have revealed that the BDNF pathway influences cognitive functions such as memory, learning and emotions.26-28 The typical transmembrane signaling induced by BDNF is mediated by high-affinity tyrosine kinase receptor B (Ntrk 2 or TrkB) and low-affinity p75 neurotrophin receptor. The intracellular cascades include mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), phospholipase C, phosphatidylinositol 3-kinase (PI3K) and the stimulation of dopamine and glutamate neurotransmission. BDNF induces presynaptic long-term potentiation and increases the postsynaptic response by increasing the conductance of NMDA receptors, increasing AMPA receptor translation and expression and reducing membrane GABA receptor expression. The identified mechanisms of action explain the important role of BDNF in neuronal plasticity and synaptic connectivity. Many authors have shown that serum BDNF concentrations may correlate with tissue BDNF levels.29-32

The neurotoxic effect of opioid has not been thoroughly described. It is known that long-term use of opiates for non-medical purposes increases the risk of psychiatric disorders, and experimental studies have also reported a negative effect on the local concentration of neurotrophic factors. Recent reports have indicated a high clinical value of BDNF levels in assessing the functional state of neurons in a group of patients with migraine, tension and cluster headaches and musculoskeletal pain.11,33,34 Moreover, no studies have been conducted to explain the effect of the opioids in chronic non-cancer pain on the neurotrophic factors level. Due to the ability to cross the blood-brain barrier, it seems that the determination of serum BDNF concentration is a reliable reflection of the concentration in the central nervous system.

The aim of the study was to explore the changes of serum BDNF concentration during long-term opioid therapy. We hypothesized that the serum BDNF level decreases in the group of patients taking opioid drugs, and the concentration of this neurotrophin depends on the opioid substance used in the therapy. In addition, we tested the hypothesis that serum BDNF value also depends on anthropometric factors and the dose of opioid used.

Patients and Methods

The study was approved by the Ethics Committee of the Medical University of Bialystok, Poland (R-I-002/307/2019) and registered at ClinicalTrials.gov (NCT04227223). The study was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. A prospective controlled cross-sectional study was conducted at Pain Clinic Vitamed, Bialystok, Poland, and the Medical University of Bialystok, Poland. Recruitment and data collection occurred between September 2019 and December 2019. All patients were recruited by direct contact from a member of the Pain Clinic staff. Patients between ages 18 years and 80 years who met chronic pain criteria due to LBP and received opioid therapy with a stable NRS (numerical rating scale) <4 were eligible for study inclusion. Patients with cognitive disorders and those receiving anti-inflammatory therapy (nonsteroidal anti-inflammatory drugs [NSAIDs], steroids, and other immunomodulatory agents) were excluded from the analysis. The patients were evaluated at Pain Clinic Vitamed, Bialystok, Poland. The control group included patients with LBP who were not receiving any pharmacotherapy. The procedures were fully explained to each participant before they were asked to sign the informed consent form. We recruited 39 patients at the beginning of our study. All patients signed informed consent forms before inclusion in the study. Age, sex, opioid substance type, daily dose, and the duration of opioid therapy were recorded.

All blood samples were processed strictly using the same protocol. The patients included in the study continued treatment with opioids and took the prescribed doses on the day the biological material was collected. After 8-10 hours of fasting and smoking abstinence, in the morning, blood samples were aseptically drawn into tubes containing ethylenediaminetetraacetic acid (2.7 mL EDTA BD vacutainers) via cubital vein puncture (21 guage needle, BD Vacutainer). Plasma was isolated after centrifugation (1000×g at 2-8 °C within 30 minutes of collection) and immediately stored at −80 °C in 300 μL aliquots in Eppendorf tubes until further analysis. The determinations were performed after 2 weeks in the Department of Biochemical Diagnostics.

A BDNF enzyme-linked immunosorbent assay (ELISA) kit was used. The values suggested by the distributor were accepted as correct. Greiner Bio-One high affinity 96-well plates were used, and absorbance was read at 450 nm in duplicate using a Bio–Rad Benchmark microplate reader. Plasma BDNF concentrations were reported as ng/ml. The coefficients of variance ranged between 2.9% and 8.1%. The lower limit of quantification was 0.61 pg/mL. The intra- and interassay coefficients of variation were <10%. The potential effect of the variation between plates/kits was eliminated by ensuring that all samples from each participant were measured using the same plate/kit. The room temperature during analyses ranged from 23.7-26.2 °C. Sample processing and data analysis were performed according to the manufacturer’s instructions (Immundiagnostik, Germany).

Statistical Analysis

The Shapiro–Wilk test was used to determine the normal distribution of continuous variables. The Mann–Whitney U test was performed for comparisons between two groups; for comparisons of more than two groups, the Kruskal–Wallis test was used. Data are presented as medians, minimum and maximum ranges and interquartile ranges. Spearman’s correlation coefficient was calculated to evaluate the correlations between anthropometric parameters and parameters connected with pharmacotherapy. The results from all patients in the study group were used to compare the BDNF concentration, while comparisons between individual opioid substances were referenced to the most numerous groups. Due to the very limited size of the study group receiving morphine and fentanyl therapy, these groups were not included in the detailed analysis. All the calculations were performed using Statistica 13.1 software. The level of significance was set to P<0.05.

Results

Included in the study were 39 patients (16 men and 23 women, median age of 67 years) with chronic low back pain. The study and control groups did not differ in characteristic parameters (Table 1). The study group consisted of patients receiving buprenorphine therapy (n=10), tramadol therapy (n=8), and oxycodone (n=6). Patients receiving morphine (n=3) and fentanyl therapy (n=1) were excluded from detailed analyses. The median duration of opioid therapy was 26 months (minimum and maximum range 12-98 months), and the median morphine equivalent was 40 mg (minimum and maximum range 7.5-160 mg). The median serum BDNF concentration in the study group was significantly lower than that in the control group (2.73 ng/mL and 5.04 ng/mL, respectively; P<0.05). BDNF serum concentrations are shown in Figure 1.

View this table:
Table 1.

Characteristic of patients included in the study and control groups

Serum BDNF concentration in study and control groups. Median, minimum and maximum, and interquartile ranges are presented. *P<0.05
Figure 1.

Serum BDNF concentration in study and control groups. Median, minimum and maximum, and interquartile ranges are presented. *P<0.05

The analysis showed that BDNF levels were similar between groups stratified based on opioid substance type, but the lowest median value was observed for patients receiving tramadol therapy (2.62 ng/mL), and the highest median value was observed for patients receiving buprenorphine therapy (2.73 ng/mL). The minimum and maximum ranges for buprenorphine were 1.36 ng/mL and 4.43 ng/mL, and for tramadol were 2.14 ng/mL and 3.48 ng/mL, respectively. The widest minimum- maximum ranges of BDNF were noted for oxycodone: minimum 1.23 ng/mL and maximum 4.57 ng/mL. Details are presented in Figure 2. Serum BDNF concentrations were correlated with age in the tramadol therapy group and with the duration of opioid therapy in the buprenorphine therapy group (Figure 3). No statistically significant correlation between the serum BDNF concentration and doses of opioid substances (morphine equivalent) was found.

Serum BDNF concentration in different opioid substances. Median, minimum and maximum, and interquartile ranges are presented.
Figure 2.

Serum BDNF concentration in different opioid substances. Median, minimum and maximum, and interquartile ranges are presented.

Figure 3.Figure 3.
View larger version:
Figure 3.

Scatter plots of the correlation between the serum BDNF concentration and (A) duration of buprenorphine therapy, and (B) age in tramadol therapy.

Discussion

The subject of neurodegeneration and immunomodulatory opioid activity is a relatively new issue, and this phenomenon is still not well known. Many conclusions are based on BDNF concentration studies in heroin-, methamphetamine-, cocaine-, and cannabis-dependent patients.35-39 Similarly, changes in BDNF levels have also been reported in nicotine-dependent patients.36,39 The results are not consistent. Luan et al37 described a mean serum BDNF level in the group of heroin-dependent patients of 1692 pg/mL, which was significantly higher than that in the control group (1194 pg/mL). Similar results were presented by other researchers.36,39 Moreover, serum BDNF levels <1251 pg/mL were associated with an increased risk of developing depression during withdrawal therapy.37 Increased serum BDNF levels were observed in patients with schizophrenia with an addiction to cannabinoid or addictive substances.40

In contrast, different results were presented by Zhang et al.38 The authors described a significantly lower mean serum BDNF level in heroin-dependent patients (987 pg/mL) both at the beginning of the study and after 26 weeks of therapy with methadone (2491 pg/mL) than that in the control group. However, the BDNF concentration increased significantly after therapy with methadone. In addition, serum BDNF levels were not associated with demographic parameters (age, body mass index, years of education, or age of first opiate use) and were not correlated with clinical factors, such as the duration of dependence. An oxidant-antioxidant imbalance, which was manifested as reduced superoxide dismutase and catalase activities and increased serum metalloprotease and tumor necrosis factor-alpha activities, has also been reported among opiate-dependent patients.33

Moreover, another study presented significant differences in BDNF levels in individuals with myofascial pain, osteoarthritis, and headache pain due to migraine attaca.41-43 Deitos et al20 suggested that BDNF was useful for identifying central sensitivity syndrome pathology, and a BDNF level > 42.83 ng/mL provided a specificity of 100%.

Many studies have indicated the use of methadone in addiction therapy exerts a positive effect on oxidative stress markers and proinflammatory cytokine levels. The authors suggested this effect depends on phospholipase D2 activation and, by reducing the synthesis of reactive oxygen species (ROS), the limited effect of the endocytosis of membrane opioid receptors and neurotoxicity.33,44-47

Few publications have examined the effect of tramadol on neuronal plasticity. One of the multidirectional pathways is weak mi-opioid receptor (MOR) activation. Tramadol, an O-desmethyltramadol metabolite, and the (+) enantiomer of tramadol act as MOR agonists and have a low affinity for delta-opioid receptor (DOR) and kappa-opioid receptor (KOR), but their analgesic potency is 1/10 that of morphine.48 Tramadol significantly increased cerebral lipid peroxidation and nitric oxide capacity, increased serum proinflammatory cytokine levels, decreased glutathione concentrations, and decreased antioxidant enzyme activity in the cerebrum. The neurotoxic effect of chronic tramadol consumption is mediated by oxidative stress, inflammation, and apoptosis. Other publications have revealed that tramadol activates atrophy and apoptosis by inducing the expression of apoptotic and proinflammatory markers, such as caspases 3 and 8, as well as glial cell line-derived neurotrophic factors. Moreover, tramadol triggers microgliosis and astrogliosis along with neuronal destruction in the prefrontal cortex.49-53

Experimental studies in animals have shown that BDNF passes through the blood–brain barrier and is measured peripherally in body fluids, serum and plasma.53,54 In the human population, 99% of the peripheral concentration is attributed to the platelet reservoir and a marginal fraction is present in the plasma.53,54 The release of BDNF from platelets during clotting processes increases the concentration of BDNF in the serum by more than 200-fold compared to assays in plasma.53,55 A correlation between an increase of 14.5% in the serum BDNF concentration for every 100x109 platelets was also reported. However, no such correlation was observed for other hematological parameters, including hematocrit.56

Measurements of serum BDNF levels have shown that a significant fraction of neurotrophin is released from platelets in the clotting process at room temperature. Moreover, most of the platelet-derived BDNF is released in the first hour of the clotting cascade. The concentration of BDNF in the serum was significantly higher than that in the plasma and was particularly higher at 60 min than at 30 min after clotting activation. However, no differences were observed in the BDNF levels measured in plasma.54 Another laboratory factor influencing the results of BDNF determinations is the storage time of the biological material. The available publications indicate the concentration of BDNF in the serum and EDTA-treated plasma remains stable for up to 6 months after their acquisition.57,58 The storage of whole blood at 4 °C significantly reduces the concentrations of this neurotrophin, and storage at −20 °C does not affect the determined parameter.59

Interesting observations also concern daily and seasonal changes in BDNF concentrations. Lower levels of this neurotrophin were recorded in January–May, while higher levels were recorded in June–December, and the lowest BDNF levels were recorded in March and the highest in August. An increasing trend was observed for the seasons of spring and summer, and a decreasing trend was observed for autumn and winter.60 In terms of the circadian rhythm, significantly lower BDNF concentrations were observed in blood samples collected in the afternoon.53,61

Additionally, anthropometric factors such as age and sex affect the BDNF concentration. Young women have higher levels of this neurotrophin. The authors suggested the dependence of the BDNF concentration on age and sex was related to the mechanism of sex hormone synthesis and, more precisely, to the dependence of BDNF synthesis on estrogen hormones. Additionally, a correlation between BDNF concentration and estrogen concentration was reported.53,59,62,63

To the best of our knowledge, this report is the first to present a correlation between serum BDNF levels and opioid therapy for chronic LBP. The main findings of this study are the significantly lower serum BDNF concentrations in the chronic opioid therapy group. We did not notice a specific association of various opioid substances with BDNF levels. However, BDNF concentrations were correlated with the duration of opioid therapy in the buprenorphine therapy group and with age in patients receiving tramadol therapy.

Several limitations of this study should be mentioned. The number of patients is too small for us to draw definitive conclusions. Additionally, we were unable to analyze all opioid substances due to the restricted recommended use of some substances in opioid therapy indications. Additionally, we did not perform any clinical test of memory or cognitive function to correlate functional tests with BDNF values.

In our pilot study, we compared the BDNF concentration in the group of patients with LBP with the healthy volunteers, and we compared the BDNF concentration in the subgroups stratified by the use of the respective opioid substances. Based on the preliminary results, we concluded that the study should be supplemented with additional information about lifestyle, coexisting hematological parameters, anticoagulant or antiplatelet therapy, and memory and cognitive function tests to obtain a comprehensive assessment of the effects of opioid drugs on the BDNF concentration. We are convinced that future studies are needed to better establish the role of BDNF concentrations in opioid use for LBP.

In conclusion, this pilot study confirmed that long-term opioid pharmacotherapy significantly changes plasma BDNF concentrations. Although we analyzed three potential substances, our results underscored the important information that opioids decrease BDNF levels. Our study confirmed that the use of buprenorphine had the least effect on changes in plasma BDNF levels.

Footnotes

  • Disclosure: The authors have not reported any conflicts of interest related to this work.

  • Received December 7, 2021.
  • Revision received August 5, 2022.
  • Accepted September 26, 2022.

References

  1. 1.
    ↵
    Franchi S, Moschetti G, Amodeo G, Sacerdote P. Do all opioid drugs share the same immunomodulatory properties? A review from animal and human studies. Front Immunol. 2019;10:2914. doi:10.3389/fimmu.2019.02914.
    Google ScholarCrossRef
  2. 2.
    ↵
    Christie MJ. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol. 2008;154(2):384-396. doi:10.1038/bjp.2008.100.
    Google ScholarCrossRefPubMedWeb of Science
  3. 3.
    ↵
    Deyo RA, Von Korff M, Duhrkoop D. Opioids for low back pain. BMJ. 2015;350(jan 05 10):g6380. doi:10.1136/bmj.g6380.
    Google ScholarCrossRefAbstract/Full TextPubMed
  4. 4.
    Morasco BJ, Duckart JP, Carr TP, Deyo RA, Dobscha SK. Clinical characteristics of veterans prescribed high doses of opioid medications for chronic non-cancer pain. Pain. 2010;151(3):625-632. doi:10.1016/j.pain.2010.08.002.
    Google ScholarCrossRefPubMedWeb of Science
  5. 5.
    ↵
    Mafi JN, McCarthy EP, Davis RB, Landon BE. Worsening trends in the management and treatment of back pain. JAMA Intern Med. 2013;173(17):1573-1581. doi:10.1001/jamainternmed.2013.8992.
    Google ScholarCrossRefPubMed
  6. 6.
    ↵
    Izzo R, Popolizio T, D’Aprile P, Muto M. Spinal pain. Eur J Radiol. 2015;84(5):746-756. doi:10.1016/j.ejrad.2015.01.018.
    Google ScholarCrossRefPubMed
  7. 7.
    Chou R, Turner JA, Devine EB, The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162(4):276-286. doi:10.7326/M14-2559.
    Google ScholarCrossRefPubMed
  8. 8.
    Maher C, Underwood M, Buchbinder R. Non-specific low back pain. Lancet. 2017;389(10070):736-747. doi:10.1016/S0140-6736(16)30970-9.
    Google ScholarCrossRefPubMed
  9. 9.
    Rieb LM, Samaan Z, Furlan AD, Canadian Guidelines on opioid use disorder among older adults. Can Geriatr J. 2020;23(1):123-134. doi:10.5770/cgj.23.420.
    Google ScholarCrossRef
  10. 10.
    ↵
    Busse JW, Wang L, Kamaleldin M, Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis. JAMA. 2018;320(23):2448-2460. doi:10.1001/jama.2018.18472.
    Google ScholarCrossRefPubMed
  11. 11.
    ↵
    Eidson LN, Murphy AZ. Inflammatory mediators of opioid tolerance: Implications for dependency and addiction. Peptides. 2019;115:51-58. doi:10.1016/j.peptides.2019.01.003.
    Google ScholarCrossRef
  12. 12.
    ↵
    Freund J, Kraus C, Hooper-Lane C. Clinical Inquiry: How effective are opioids for chronic low back pain? J Fam Pract. 2015;64(9):584-585.
    Google Scholar
  13. 13.
    Rauck RL. What is the case for prescribing long-acting opioids over short-acting opioids for patients with chronic pain? A critical review. Pain Pract. 2009;9(6):468-479. doi:10.1111/j.1533-2500.2009.00320.x.
    Google ScholarCrossRefPubMed
  14. 14.
    Siddall PJ, Cousins MJ. Persistent pain as a disease entity: implications for clinical management. Anesth Analg. 2004;99(2):510-520. doi:10.1213/01.ANE.0000133383.17666.3A.
    Google ScholarCrossRefPubMedWeb of Science
  15. 15.
    Varrassi G, Fusco M, Skaper SD, A pharmacological rationale to reduce the incidence of opioi-induced tolerance and hyperalgesia. A review. Pain Ther. 2018;7(1):59-75. doi:10.1007/s40122-018-0094-9.
    Google ScholarCrossRef
  16. 16.
    ↵
    Zhang K, Jiang H, Zhang Q, Du J, Wang Y, Zhao M. Brain-derived neurotrophic factor serum levels in heroin-dependent patients after 26weeks of withdrawal. Compr Psychiatry. 2016;65:150-155. doi:10.1016/j.comppsych.2015.11.010.
    Google ScholarCrossRef
  17. 17.
    ↵
    Langlois LD, Nugent FS. Opiates and Plasticity in the Ventral Tegmental Area. ACS Chem Neurosci. 2017;8(9):1830-1838. doi:10.1021/acschemneuro.7b00281.
    Google ScholarCrossRef
  18. 18.
    Akbarian S, Rios M, Liu RJ, Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons. J Neurosci. 2002;22(10):4153-4162. doi:10.1523/JNEUROSCI.22-10-04153.2002.
    Google ScholarCrossRefAbstract/Full TextPubMedWeb of Science
  19. 19.
    Wen YR, Tan PH, Cheng JK, Liu YC, Ji RR. Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. J Formos Med Assoc. 2011;110(8):487-494. doi:10.1016/S0929-6646(11)60074-0.
    Google ScholarCrossRefPubMed
  20. 20.
    ↵
    Deitos A, Dussán-Sarria JA, Souza Ad, Clinical Value of Serum Neuroplasticity Mediators in Identifying the Central Sensitivity Syndrome in Patients With Chronic Pain With and Without Structural Pathology. Clin J Pain. 2015;31(11):959-967. doi:10.1097/AJP.0000000000000194.
    Google ScholarCrossRef
  21. 21.
    Przewlocka B. Basic mechanisms of analgesic effects of opioids. Palliative Medicine in Practice. 2017;2:48-54.
    Google Scholar
  22. 22.
    Grosser T, Woolf CJ, FitzGerald GA. Time for nonaddictive relief of pain. Science. 2017;355(6329):1026-1027. doi:10.1126/science.aan0088.
    Google ScholarCrossRefAbstract/Full TextPubMed
  23. 23.
    Connock M, Juarez-Garcia A, Jowett S, Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess. 2007;11(9):1-171, iii-iv. doi:10.3310/hta11090.
    Google ScholarCrossRefPubMed
  24. 24.
    ↵
    Subedi M, Bajaj S, Kumar MS, Yc M. An overview of tramadol and its usage in pain management and future perspective. Biomed Pharmacother. 2019;111:443-451. doi:10.1016/j.biopha.2018.12.085.
    Google ScholarCrossRefPubMed
  25. 25.
    ↵
    Barde YA, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1(5):549-553. doi:10.1002/j.1460-2075.1982.tb01207.x.
    Google ScholarCrossRefPubMedWeb of Science
  26. 26.
    ↵
    Corominas M, Roncero C, Ribases M, Castells X, Casas M. Brain-derived neurotrophic factor and its intracellular signaling pathways in cocaine addiction. Neuropsychobiology. 2007;55(1):2-13. doi:10.1159/000103570.
    Google ScholarCrossRefPubMedWeb of Science
  27. 27.
    Barker JM, Taylor JR, De Vries TJ, Peters J. Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking. Brain Res. 2015;1628(Pt A):68-81. doi:10.1016/j.brainres.2014.10.058.
    Google ScholarCrossRef
  28. 28.
    ↵
    Khan AN, Jacobsen HE, Khan J, Inflammatory biomarkers of low back pain and disc degeneration: a review. Ann N Y Acad Sci. 2017;1410(1):68-84. doi:10.1111/nyas.13551.
    Google ScholarCrossRefPubMed
  29. 29.
    ↵
    Cappoli N, Tabolacci E, Aceto P, Dello Russo C. The emerging role of the BDNF-TrkB signaling pathway in the modulation of pain perception. J Neuroimmunol. 2020;349:577406. doi:10.1016/j.jneuroim.2020.577406.
    Google ScholarCrossRef
  30. 30.
    Cao T, Matyas JJ, Renn CL, Faden AI, Dorsey SG, Wu J. Function and mechanisms of truncated BDNF receptor TrkB.T1 in neuropathic pain. Cells. 2020;9(5):1194. doi:10.3390/cells9051194.
    Google ScholarCrossRef
  31. 31.
    Sartorius A, Hellweg R, Litzke J, Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats. Pharmacopsychiatry. 2009;42(06):270-276. doi:10.1055/s-0029-1224162.
    Google ScholarCrossRefPubMedWeb of Science
  32. 32.
    ↵
    Lang UE, Hellweg R, Seifert F, Schubert F, Gallinat J. Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity. Biol Psychiatry. 2007;62(5):530-535. doi:10.1016/j.biopsych.2007.01.002.
    Google ScholarCrossRefPubMedWeb of Science
  33. 33.
    ↵
    Salarian A, Kadkhodaee M, Zahmatkesh M, Opioid Use Disorder Induces Oxidative Stress and Inflammation: The Attenuating Effect of Methadone Maintenance Treatment. Iran J Psychiatry. 2018;13(1):46-54.
    Google Scholar
  34. 34.
    ↵
    Björkholm C, Monteggia LM. BDNF – a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72-79. doi:10.1016/j.neuropharm.2015.10.034.
    Google ScholarCrossRefPubMed
  35. 35.
    ↵
    Bayazit H, Dulgeroglu D, Selek S. Brain-derived neurotrophic factor and oxidative stress in cannabis dependence. Neuropsychobiology. 2020;79(3):186-190. doi:10.1159/000504626.
    Google ScholarCrossRef
  36. 36.
    ↵
    Machaalani R, Chen H. Brain derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB) and nicotine. Neurotoxicology. 2018;65:186-195. doi:10.1016/j.neuro.2018.02.014.
    Google ScholarCrossRefPubMed
  37. 37.
    ↵
    Luan X, Tao J, Zhang J, Increased BDNF may not be associated with cognitive impairment in heroin-dependent patients. Medicine (Baltimore). 2017;96(15):e6582. doi:10.1097/MD.0000000000006582.
    Google ScholarCrossRef
  38. 38.
    ↵
    Zhang J, Zhang X, Su H, Increased serum brain-derived neurotrophic factor levels during opiate withdrawal. Neurosci Lett. 2014;571:61-65. doi:10.1016/j.neulet.2014.04.048.
    Google ScholarCrossRef
  39. 39.
    ↵
    Huang Z, Wu D, Qu X, Li M, Zou J, Tan S. BDNF and nicotine dependence: associations and potential mechanisms. Rev Neurosci. 2020;/j/revneuro.ahead-of-print/revneuro-2020-0044/revneuro-2020-0044.xml. doi:10.1515/revneuro-2020-0044.
    Google ScholarCrossRef
  40. 40.
    ↵
    Jockers-Scherübl MC, Danker-Hopfe H, Mahlberg R, Brain-derived neurotrophic factor serum concentrations are increased in drug-naïve schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci Lett. 2004;371(1):79-83. doi:10.1016/j.neulet.2004.08.045.
    Google ScholarCrossRefPubMed
  41. 41.
    ↵
    Fischer M, Wille G, Klien S, Brain-derived neurotrophic factor in primary headaches. J Headache Pain. 2012;13(6):469-475. doi:10.1007/s10194-012-0454-5.
    Google ScholarCrossRefPubMedWeb of Science
  42. 42.
    Tanure MTA, Gomez RS, Hurtado RCL, Teixeira AL, Domingues RB. Increased serum levels of brain-derived neurotropic factor during migraine attacks: a pilot study. J Headache Pain. 2010;11(5):427-430. doi:10.1007/s10194-010-0233-0.
    Google ScholarCrossRefPubMedWeb of Science
  43. 43.
    ↵
    Bachis A, Campbell LA, Jenkins K, Wenzel E, Mocchetti I. Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor. Neurotox Res. 2017;32(3):509-517. doi:10.1007/s12640-017-9788-8.
    Google ScholarCrossRef
  44. 44.
    ↵
    Wang TY, Lee SY, Chang YH, Correlation of cytokines, BDNF levels, and memory function in patients with opioid use disorder undergoing methadone maintenance treatment. Drug Alcohol Depend. 2018;191:6-13. doi:10.1016/j.drugalcdep.2018.06.024.
    Google ScholarCrossRef
  45. 45.
    Lu RB, Wang TY, Lee SY, Correlation between interleukin-6 levels and methadone maintenance therapy outcomes. Drug Alcohol Depend. 2019;204:107516. doi:10.1016/j.drugalcdep.2019.06.018
    Google ScholarCrossRef
  46. 46.
    O Ornell F, Hansen F, Schuch FB, Brain-derived neurotrophic factor in substance use disorders: A systematic review and meta-analysis. Drug Alcohol Depend. 2018;193:91-103. doi:10.1016/j.drugalcdep.2018.08.036.
    Google ScholarCrossRef
  47. 47.
    ↵
    Filipczak-Bryniarska I, Nazimek K, Nowak B, Kozlowski M, Wąsik M, Bryniarski K. In contrast to morphine, buprenorphine enhances macrophage-induced humoral immunity and, as oxycodone, slightly suppresses the effector phase of cell-mediated immune response in mice. Int Immunopharmacol. 2018;54:344-353. doi:10.1016/j.intimp.2017.11.039.
    Google ScholarCrossRef
  48. 48.
    ↵
    Yang C, Li X, Wang N, Xu S, Yang J, Zhou Z. Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in rat hippocampus. Front Med. 2012;6(4):411-415. doi:10.1007/s11684-012-0226-2.
    Google ScholarCrossRef
  49. 49.
    ↵
    Mohamed HM, Mahmoud AM. Chronic exposure to the opioid tramadol induces oxidative damage, inflammation and apoptosis, and alters cerebral monoamine neurotransmitters in rats. Biomed Pharmacother. 2019;110:239-247. doi:10.1016/j.biopha.2018.11.141.
    Google ScholarCrossRef
  50. 50.
    Raj K, Chawla P, Singh S. Neurobehavioral Consequences Associated with Long Term Tramadol Utilization and Pathological Mechanisms. CNS Neurol Disord Drug Targets. 2020;18(10):758-768. doi:10.2174/1871527318666191112124435.
    Google ScholarCrossRef
  51. 51.
    Bravo L, Mico JA, Berrocoso E. Discovery and development of tramadol for the treatment of pain. Expert Opin Drug Discov. 2017;12(12):1281-1291. doi: 10.1080/17460441.2017.1377697.
    Google ScholarCrossRef
  52. 52.
    Aghajanpour F, Boroujeni ME, Jahanian A, Tramadol: a Potential Neurotoxic Agent Affecting Prefrontal Cortices in Adult Male Rats and PC-12 Cell Line. Neurotox Res. 2020;38(2):385-397. doi:10.1007/s12640-020-00214-z.
    Google ScholarCrossRef
  53. 53.
    ↵
    Bus BA, Tendolkar I, Franke B, Serum brain-derived neurotrophic factor: determinants and relationship with depressive symptoms in a community population of middle-aged and elderly people. World J Biol Psychiatry. 2012;13(1):39-47. doi:10.3109/15622975.2010.545187.
    Google ScholarCrossRefPubMed
  54. 54.
    ↵
    Gejl AK, Enevold C, Bugge A, Andersen MS, Nielsen CH, Andersen LB. Associations between serum and plasma brain-derived neurotrophic factor and influence of storage time and centrifugation strategy. Sci Rep. 2019;9(1):9655. doi:10.1038/s41598-019-45976-5.
    Google ScholarCrossRef
  55. 55.
    ↵
    Rozenfeld RD, Zeni L, Haniu H, Purification and identification of BDNF from human serum. Protein Expr Purif. 1995;6:465-471. doi:10.1006/prep.1995.1062.
    Google ScholarCrossRefPubMedWeb of Science
  56. 56.
    ↵
    Naegelin Y, Dingsdale H, Säuberli K, Schädelin S, Kappos L, Barde YA. Measuring and Validating the Levels of Brain-Derived Neurotrophic Factor in Human Serum. eNeuro. 2018;5(2):ENEURO.0419-17.2018. doi:10.1523/ENEURO.0419-17.2018.
    Google ScholarCrossRefAbstract/Full TextPubMed
  57. 57.
    ↵
    A Amadio P, Sandrini L, Ieraci A, Tremoli E, Barbieri SS. Effect of Clotting Duration and Temperature on BDNF Measurement in Human Serum. Int J Mol Sci. 2017;18(9):1987. doi:10.3390/ijms18091987.
    Google ScholarCrossRef
  58. 58.
    ↵
    Polyakova M, Schlögl H, Sacher J, Stability of BDNF in human samples stored up to 6 months and correlations of serum and EDTA-plasma concentrations. Int J Mol Sci. 2017;18(6):1189. doi:10.3390/ijms18061189.
    Google ScholarCrossRef
  59. 59.
    ↵
    Trajkovska V, Marcussen AB, Vinberg M, Hartvig P, Aznar S, Knudsen GM. Measurements of brain-derived neurotrophic factor: Methodological aspects and demographical data. Brain Res Bull. 2007;73(1-3):143-149. doi:10.1016/j.brainresbull.2007.03.009.
    Google ScholarCrossRefPubMedWeb of Science
  60. 60.
    ↵
    Molendijk ML, Haffmans JP, Bus BA, Serum BDNF concentrations show strong seasonal variation and correlations with the amount of ambient sunlight. PLoS One. 2012;7(11):e48046. doi:10.1371/journal.pone.0048046
    Google ScholarCrossRefPubMed
  61. 61.
    ↵
    Piccinni A, Marazziti D, Del Debbio A, Diurnal variation of plasma brain-derived neurotrophic factor (BDNF) in humans: an analysis of sex differences. Chronobiol Int. 2008;25(5):819-826. doi:10.1080/07420520802387773.
    Google ScholarCrossRefPubMedWeb of Science
  62. 62.
    ↵
    Becker JB, Chartoff E. Sex differences in neural mechanisms mediating reward and addiction. Neuropsychopharmacology. 2019;44(1):166-183. doi:10.1038/s41386-018-0125-6.
    Google ScholarCrossRefPubMed
  63. 63.
    ↵
    Lopes GS, Bielinski S, Moyer AM, Sex differences in type and occurrence of adverse reactions to opioid analgesics: a retrospective cohort study. BMJ Open. 2021;11(6):e044157. doi:10.1136/bmjopen-2020-044157.
    Google ScholarCrossRefAbstract/Full TextPubMed
Loading
Back to top
In this Issue
Clinical Medicine & Research
Clinical Medicine & Research

Vol. 20, Issue 4

1 Dec 2022

Table of Contents Cover (Photo) Index by author
Jump to

Keywords

Chronic pain, Neurotoxicity, Opioids