Applied nutritional investigationTolerance and efficacy of a polyamine-deficient diet for the treatment of perioperative pain
Introduction
Lower back pain, with or without leg pain, is a notably common problem that effects up to 85% of adults and has a negative impact on work productivity and quality of life [1], [2]. It may lead to a history of pain sensitization and long-term use of pain medication. Lumbar spinal stenosis surgery (LSS) is a perfect surgical example of the complex situation when nociceptive (i.e., low back pain), inflammatory (i.e., articular hypertrophy), and neuropathic pain (i.e., neurogenic pain) combine to result in substantial psychological and/or social consequences [3]. In this case, the postoperative outcomes remain partially satisfactory (i.e., persistent chronic postoperative pain) [4].
Excitation of N-methyl-D-aspartate (NMDA) receptors was considered a straightforward process that evolved to maximize the rate of neuronal communication. It was recently reported that NMDA receptors might play an important role in pain and/or hyperalgesia phenomena, particularly in pain memorization and pain sensitization. In a recent review, it was reported that ketamine has an opioid sparing effect, particularly in painful procedures [5], that is mainly due to the inhibition of NMDA receptors [6]. Many different NMDA receptor subtypes coexist in the central nervous system [7]. Usually localized in postsynaptic sites, they are mobile with various levels of conductance channels modulated by protons, polyamines (PA), and magnesium.
PA (putrescine, spermidine, and spermine) are ubiquitous small cationic organic molecules [8]. They contribute to the control of neuronal excitability. PA acts on tyrosine phosphorylation of NMDA receptor subtype-2 B as a scaffolding element of neuroplasticity [7]. PA has been intensively investigated, and their link to several pathologies has been well established [8]. In addition to their well-known universal role in cell division and proliferation, PA are involved in additional biological processes, such as tumor growth [9] and inflammatory processes [10]. Interesting preliminary clinical results were recently described in the treatment of prostate cancer [11], [12]. PA were recently shown to regulate the formation of mRNA stress granules [13]. Apart from being endogenously synthesized, an exogenous supply of PA by intestinal uptake is generally assumed to be the predominant PA transport pathway. PA intestinal absorption occurs through dietary sources (80%) and intestinal absorption from bacterial metabolism [14], [15]. Because intestinal absorption is a critical source of PA, an obvious link between food and PA concentration has been suggested. Based on recent animal studies, researchers have proposed that certain “Functional Foods” (defined as foods or food components that may provide health benefits beyond traditional nutrition) may represent a promising and safe strategy for improving the management of pain in combination with analgesic drugs classically used [16]. However, establishing such a proof of concept in humans has never been specifically considered and in particular for perioperative pain. In a previous experimental model, it was reported that a polyamine-deficient diet (PDD) had preventive properties against pain hypersensitivity [17], oxaliplatine-induced sensory neuropathy [18], and had a curative effect on heroin-induced hyperalgesia in a rat model [19].
To test the hypothesis that a PDD could have an effect on perioperative pain in humans, we designed a study by building on the experience gained in clinical trials on prostate cancer treatment [11], [12]. We planned a prospective, randomized, multicenter, and blinded phase II clinical trial following the intention-to-treat principle with the pain level as primary endpoint.
Section snippets
Study design and patients
The study design was built on previous clinical observations made with patients suffering from chronic non-malignant pain [20] and in castrate-resistant prostate cancer [12]. A significant decrease in the pain scores was observed when patients were under strict PDD, i.e., 80% of the food intake calories were provided by the food for special medical purposes, specifically Polydol, which is characterized by a low PA content. Conversely, no effect on pain was observed when patients were only under
Results
Between September 2009 and September 2012, 64 patients recruited by seven participating hospitals were randomized. After the exclusion of two patients (one patient withdrew consent before treatment in group 1 and one withdrew for cancelled surgery due to cancer diagnosis in group 2), 60 patients were analyzed in ITT (one patient in each group was excluded from the ITT analysis because of the use of steroids) (Fig. 1).
Discussion
We found that the PDD using Polydol had pain reduction effects on perioperative (i.e., pre and early postoperative) pain in the current clinical study. This is the very first randomized multicenter clinical trial confirming this new approach for the management of chronic pain. Our clinical data reinforce results from previously reported preliminary studies [12], [20]. We choose to use a control group with partial PDD because we known that a partial PDD is not enough to induce a sufficient
Conclusion
Suppression of polyamines from the diet may be an important mechanism of preoperative and/or early postoperative (hyperalgesia) reduction independent of the usual analgesic approaches. With good tolerance and compliance, a polyamine-deficient diet could be a new and safer technique for the treatment and/or the prevention of postoperative pain. Due to active patient participation, a polyamine diet could be part of the therapeutic education of chronic pain patients or be part of prehabilitation
References (32)
Non-opioid IV adjuvants in the perioperative period: Pharmacological and clinical aspects of ketamine and gabapentinoids
Pharm Res
(2012)- et al.
Role of peripheral polyamines in the development of inflammatory pain
Biochem Pharmacol
(2011) - et al.
Polyamine reduced diet nutrition therapy in hormone refractory prostate cancer patients
Biomed Pharmacother
(2010) - et al.
Biological significance of dietary polyamines
Nutrition
(2007) Food and pain: Should we be more interested in what our patients eat?
Pain
(2007)- et al.
A polyamine-deficient diet opposes hyperalgesia, tolerance and the increased anxiety-like behavior associated with heroin withdrawal in rats
Pharmacol Biochem Behav
(2013) - et al.
Preoperative prediction of severe postoperative pain
Pain
(2003) - et al.
Delayed aversive effects of high-dose fentanyl. Prevention by a polyamine-deficient diet
Behav Brain Res
(2008) - et al.
Development of a polyamine database for assessing dietary intake
J Am Diet Assoc
(2007) - et al.
Dietary polyamine intake and risk of colorectal adenomatous polyps
Am J Clin Nutr
(2012)
The rising prevalence of chronic low back pain
Arch Intern Med
Low back pain hospitalization. Recent United States trends and regional variations
Spine
Pain intensity on the first day after surgery: A prospective cohort study comparing 179 surgical procedures
Anesthesiology
Instrumentation in lumbar fusion improves back pain but not quality of life 2 years after surgery
Acta Orthop
A systematic review of intravenous ketamine for postoperative analgesia
Can J Anaesth
NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease
Nat Rev Neurosci
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Has human diet a role in reducing nociception related to inflammation and chronic pain?
2019, NutritionCitation Excerpt :Polyamines are a good example of the complexity with which such ubiquitous molecules are involved in an increase in pain phenomena despite the ability to dampen nociception in certain complex conditions. For example, polyamines target the NMDA receptor [72,73]. In this context, polyamine-deficient diets are dietary and therapeutic tools against pain [74].
Nutritional intervention in chronic pain: an innovative way of targeting central nervous system sensitization?
2020, Expert Opinion on Therapeutic TargetsCell-based therapies and natural compounds for pain
2018, Australian Endodontic Journal
Institutional Review Board: Comité de protection de personnes Ouest VI: Centre hospitalier Universitaire Cavale Blanche; Avenue Tanguy Prigent; 29609 Brest Cedex France. Chair Doctor Mariannick Le Bot. CPP Ouest 6-592; ref file: NTL_RACHIS_09/2 ALGIE1. Number EudraCT: 2009-A00504-53. E-mail address: [email protected]; Fax: 33 2983 42579. Tel.: 33 2983 42580. CPP Ouest VI: CHU Cavale Blanche; Avenue T Prigent; 29609 Brest Cedex France. CPP Ouest 6-592; ref file: NTL_RACHIS_09/2 ALGIE1. Number EudraCT: 2009-A00504-53. [email protected]. Jean-Pierre Estebe had a patent from the University of Rennes 1 (07703762.02114 PCT/EP2007050215; European Patents 1973425 B1; 10.03.2010) and is a shareholder in Nutrialys Medical Nutrition SA. He was in charge of designing the study protocol but did not participate as an investigator in the study and did not contribute to the recording of the data or the statistical evaluation. The study was supported by Nutrialys Medical Nutrition SA. The sponsor was not involved in the design of the study, data analysis, data interpretation, or the writing of the clinical report. They also did not have access to the clinical trial database. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit the report for publication. Designed the study and oversaw data collection and verification: J-P.E. Enrolled patients and collected the data: C.D., G.R., F.D., G.D., A.L., A.B., P.S., A.L.S. Analyzed and interpreted the data and wrote the initial draft: A.L.S., J-P.E. All authors critically ensured the accuracy of the data and analysis, reviewed the draft and approved the final version of the manuscript for submission.