Elsevier

Nutrition

Volume 36, April 2017, Pages 33-40
Nutrition

Applied nutritional investigation
Tolerance and efficacy of a polyamine-deficient diet for the treatment of perioperative pain

https://doi.org/10.1016/j.nut.2016.02.018Get rights and content

Highlights

  • Polyamines diet offers a nutrition-based treatment option for perioperative pain reduction.

  • The compliance and tolerance of this total diet were very good during the pre and postoperative period.

  • It is noteworthy that pain reduction induced by total polyamines diet (compared to partial diet) was relatively quick with a significant effect reported during the preoperative period.

  • Interestingly, this diet seems to be more effective for the higher levels of pain.

  • The major mechanism of action is most likely due to an inhibition of tyrosine phosphorylation of the NMDA receptors.

Abstract

Background

Polyamines have been identified as pain agonists and interact with N-methyl-D-aspartate receptors. A prospective, randomized, multicenter, and blinded phase II clinical trial was conducted to evaluate a polyamine-deficient diet for the treatment of perioperative pain in patients during spinal surgery.

Methods

All analyses followed the intention-to-treat principle. The trial was designed to evaluate the dose-ranging effect of a low polyamine diet with respect to a total (group 1) or partial (group 2) polyamine diet on perioperative pain (7 d before and 5 d after surgery). Pain (numerical scale at rest and motion), quality of life questionnaires (Brief Pain Inventory, EIFEL questionnaire, and Short Form-12 acute questionnaire), and tolerance of and compliance with the nutritional program were measured.

Results

Compliance (preoperatively: 100% in group 1 and 83% in group 2; postoperatively: 83% in group 1 and 71% in group 2) and tolerance were good. After 7 d following the diet before surgery, decreased pain was observed in group 1 whereas no effect was observed in group 2 (P = 0.144). This analgesic effect became significant in group 1 in the subgroup of patients with initial high levels of pain (NS ≥ 4) at rest (P = 0.03) and during motion (P = 0.011). Quality of life was significantly improved in group 1 (P = 0.0465). In the postoperative period, pain was significantly decreased in group 1 compared to group 2 at rest (P = 0.022) and during motion (P = 0.029). The effect was significantly better on patients with higher initial pain both at rest (P = 0.013) and during motion (P = 0.005) in group 1 compared to group 2.

Conclusion

Suppression of polyamines from the diet offers a nutrition-based treatment option for perioperative pain reduction independent of and complementary to typical analgesic approaches.

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

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    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.

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