Water

Water is the essential constituent of the human organism and is indispensable for the conduct of all physiological processes and biochemical reactions. Adequate water intake depends on many factors, such as age, sex, environmental conditions, activity level and level of sweating. It is helpful to drink about 1·5–2 litres daily, as specified in the latest revision of the Guidelines for Healthy Eating in 2003^{( 20 )}.

Two recent studies have analysed the effects of dehydration on pain in healthy subjects by the ‘cold pressor test’ (CPT). Hypohydration can change the cerebrovascular response to CPT⁽ Reference Perry, Bear and Lucas ^{21 )}, resulting in increased pain sensitivity⁽ Reference Bear, Philipp and Hill ^{22 )}. The mechanism underpinning the increase in pain perception due to hypohydration is unclear: the key factor causing the increase in pain centre activity is activated by the subjective feeling of thirst within a multimodal network designed to detect negative sensory inputs. An alternative, or possibly related, explanation of the increase in pain perception induced by hypohydration involves cortisol, as blood cortisol concentrations are increased by hypohydration. Pain perception is linked directly to cortisol and may be indirectly linked by cortisol’s involvement in key pain regulation processes such as regulation of the immune system and testosterone production, which may reduce pain by suppressing activity in the thalamus and middle frontal; therefore, cortisol may increase pain perception by lowering testosterone⁽ Reference Bear, Philipp and Hill ^{22 )}.

Osteopathic treatment improves pain symptoms and the effect may be greater in euhydration than hypohydration⁽ Reference Parker and Kappler ^{23 )}.

Online supplementary Table S1 summarises the studies investigating the role of water intake in chronic pain subjects.

In conclusion, hydration status is significantly correlated with pain; therefore, water is at the base of the pyramid.

Fruits and vegetables

Assmann et al. ⁽ Reference Assmann, Lassale and Andreeva ^{24 )} underline that, during midlife, the adherence to a healthy diet that provides micronutrients, fibre and antioxidants while regulating energy intake may help to promote healthy ageing. Also the Dietary Approaches to Stop Hypertension (DASH) diet exerts an important role in preventing inflammatory disease, because of its low saturated fat content and emphasis on eating an abundance of fruits and vegetables.

Consumption of fruits and vegetables, which contain many vitamins, minerals and antioxidants, is inversely associated with inflammation and oxidative stress in adults: the higher the consumption of vegetables, the lower the occurrence of inflammation and oxidative stress⁽ Reference Miller, Erlinger and Sacks ^{25 –} Reference Delichatsios and Welty ^{28 )}: Miller et al. ⁽ Reference Miller, Erlinger and Sacks ^{25 )} evaluated the difference between a typical American diet and a DASH diet (rich in fruit and vegetables) and they observed that the second one reduced oxidative stress (urinary isoprostanes) yet increased antibodies to oxidation of LDL.

Some researchers have focused their attention on the decrease in C-reactive protein (CRP) levels associated with diets rich in fruits and vegetables⁽ Reference Bhupathiraju and Tucker ^{29 –} Reference Oliveira, Rodriguez-Artalejo and Lopes ^{31 )}. These three studies reached their conclusions based on FFQ.

Holt et al. ⁽ Reference Holt, Steffen and Moran ^{32 )} investigated this association in adolescents, confirming the results obtained for adults: the consumption of fruit and vegetables was inversely correlated with markers of inflammation (CRP, IL-6, TNF-α and 15-keto-dihydro-PGF2α metabolite) and oxidative stress (urinary 8-iso PG F2α, an F2-isoprostane) tested with a FFQ.

The inflammation reduction is secondary to the content in fruits and vegetables of high amounts of fibre, micronutrients (such as vitamins C and E, and folate) and phytochemicals (such as carotenoids, phenolics, isoflavones and indoles). In addition, intake of fruits and vegetables stimulates the production of butyrate, produced by bacterial fermentation of dietary fibre in the colon, which reduces inflammation of the mucosa by decreasing the activity of NF-κB in colonic cells in patients with ulcerative colitis⁽ Reference Lührs, Gerke and Müller ^{33 )}.

Flavonoids (in citrus fruits, apples, berries, tomatoes, fennel, cauliflower, etc.) appear to be involved in maintaining the sealing of intercellular junctions, which are part of the main determinants of the intestinal barrier function⁽ Reference Suzuki and Hara ^{34 )}.

Online Supplementary Table S2 summarises the studies that investigate the relationship between intake of fruits and vegetables and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers.

In conclusion, the literature is sufficient to demonstrate that fruit and vegetable consumption is inversely associated with pro-inflammatory cytokines and reactive oxygen species, secondary to inflammation and oxidative stress in adults. In order to reduce pro-inflammatory cytokines and reactive oxygen species, a daily intake of five portions of fruits and vegetables is recommended.

Carbohydrates with low glycaemic index/load

The consumption of high-glycaemic index food may contribute to oxidative stress and low-grade inflammation, both in acute and chronic pain, through changes in NF-κB⁽ Reference Dickinson, Hancock and Petocz ^{35 )}. An excessive postprandial glucose excursion causes the generation of NO, which in turn combines with superoxide to produce peroxynitrite, a potent and long-lived pro-oxidant molecule⁽ Reference Ceriello ^{36 )}.

Fardet⁽ Reference Fardet ^{37 )} analysed the components of whole grains that have low glycaemic index, and concluded that these foods are rich in various bioactive compounds (polyphenols, phytic acid and lignin) with anti-inflammatory properties, including the reduction of free radicals and the activation of antioxidant enzymes, but the author underlined the necessity of other studies to determine the mechanisms involved.

These associations were further confirmed in a recent study, which compared a low-glycaemic index with a high-glycaemic index diet: in this study patients were randomised to different diets⁽ Reference Gögebakan, Kohl and Osterhoff ^{38 )}. A dietary approach with foods with a low glycaemic index is more effective in regard to the reduction of chronic inflammation, taking as the first outcome high-sensitivity CRP, whereas glycaemic peaks are one of the main causes of oxidative stress⁽ Reference Gögebakan, Kohl and Osterhoff ^{38 )}. In line with this, Ebbeling et al. ⁽ Reference Ebbeling, Swain and Feldman ^{39 )} observed lower concentrations of CRP following a low-glycaemic index diet compared with a higher-glycaemic index diet.

Online Supplementary Table S3 summarises the studies investigating the relationship between carbohydrate intake with a low glycaemic index (<70) and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, all conditions present in chronic pain subjects.

In conclusion, it is recommended to take daily whole grains (three portions of whole grains, for example whole rice or Basmati rice or Doongara rice or rolled oats) in order to lower glycaemic index and load of the diet.

Olive oil and olives

The main source of lipid intake in the Mediterranean diet is represented by extra virgin olive oil (EVO). The intake of these lipids (rich in MUFA) has been recognised as an important factor contributing to the positive health profile characteristic of the Mediterranean population, because they have anti-inflammatory, antimicrobial and antioxidant activity⁽ Reference Tripoli, Giammanco and Tabacchi ^{40 )}.

The high concentration of MUFA and many bioactive compounds (such as polyphenols) are mainly responsible for its anti-inflammatory properties; other seed oils do not have the same health benefits as EVO, as demonstrated by the study of Harper et al. ⁽ Reference Harper, Edwards and Jacobson ^{41 )} in which a supplementation of α-linolenic acid (ALA) of flaxseed oil did not decrease CVD risk, and by the study of Aguilera et al. ⁽ Reference Aguilera, Mesa and Ramirez-Tortosa ^{42 )} in which a supplementation of sunflower-seed oil did not protect as olive oil⁽ Reference Harper, Edwards and Jacobson ^{41 ,} Reference Aguilera, Mesa and Ramirez-Tortosa ^{42 )}.

Lignans are the main components of the phenolic fraction of polyphenols in EVO⁽ Reference Owen, Mier and Giacosa ^{43 )} and the main representatives are acetoxipinoresinol and pinoresinol.

Despite the different concentrations among different EVO oils, lignans are present in greater quantities than other phenolic components, in a range between 0·65 and 99·97 mg/kg⁽ Reference Owen, Mier and Giacosa ^{44 )}. The anti-inflammatory properties of bioactive compounds of EVO could explain why the incidence of cancer and heart diseases is lower in the Mediterranean basin than in other geographic areas⁽ Reference Owen, Giacosa and Hull ^{45 )}.

Also, nutraceutical properties of EVO have been attributed to secoiridoids, such as oleuropein and its derivatives, the main alcohols 3,4-dihydroxyphenyl ethanol, also known as hydroxytyrosol and the p-hydroxyphenyl ethanol or tyrosol⁽ Reference Tripoli, Giammanco and Tabacchi ^{40 ,} Reference Bendini, Cerretani and Carrasco-Pancorbo ^{46 )}.

In addition, these phenolic components from EVO, in many preclinical models of disease, show a great variety of beneficial effects, mainly related to their antioxidant activity⁽ Reference Omar ^{47 –} Reference Hu, He and Jiang ^{52 )}. Oleuropein has an anti-inflammatory effect thanks to the increase in NO production, in macrophages and inhibiting lipoxygenase activity and the production of leukotriene B4⁽ Reference Omar ^{47 –} Reference Visioli, Poli and Gall ^{51 )}.

Moreover, oleuropein and hydroxytyrosol have vasodilator properties, anti-inflammatory activity and an anti-aggregating action on platelets⁽ Reference Omar ^{47 –} Reference Cicerale, Lucas and Keast ^{50 ,} Reference Omar ^{53 ,} Reference Cicerale, Conlan and Sinclair ^{54 )}.

Decarboxymethyl-aglycone ligstroside or oleocanthal is a phenolic compound that mimics the inhibitory action of cyclo-oxygenase (COX) by the NSAID ibuprofen, as a natural NSAID⁽ Reference Beauchamp, Keast and Morel ^{55 )}.

Oleocanthal was identified in the secoiridoid fraction of EVO phenolic compounds⁽ Reference Cicerale, Conlan and Sinclair ^{54 )} and described as the compound responsible for oropharyngeal irritation associated with EVO intake⁽ Reference Montedoro, Servili and Baldioli ^{56 )}, perceptually similar to the irritation caused by ibuprofen⁽ Reference Andrewes, Busch and de Joode ^{57 ,} Reference Cicerale, Breslin and Beauchamp ^{58 )}.

Subsequently, in a study by Beauchamp et al. ⁽ Reference Beauchamp, Keast and Morel ^{55 )}, oleocanthal showed dose-dependent inhibition of the inflammatory enzymes COX-1 and COX-2 more powerful, in equimolar concentrations, as compared with ibuprofen.

Obviously the fruit olive (Olea europaea), from which EVO is derived by cold pressing, has significant anti-inflammatory and antinociceptive activities due to the presence of many phenolic compounds (among these the most important are hydroxytyrosol and tyrosol)⁽ Reference Sahranavard, Kamalinejad and Faizi ^{59 )}. Takeda et al. ⁽ Reference Takeda, Koike and Taniguchi ^{60 )} treated a group of twenty-five individuals with early-stage knee osteoarthritis: hydroxytyrosol was effective in improving pain in gonarthrosis, measuring with the Japanese Orthopedic Association score and a visual analogue scale score compared with the placebo group. Moreover, olive pits have cholinergic activity as demonstrated by the study of Cortés Castell et al. ⁽ Reference Cortés Castell, Galindo and Montell ^{61 )} who determined the effect of a polyphenolic extract from olive pits on the development of the nervous system as well as its effect on pain induced by the neurotoxin kainic acid, taking the zebrafish as the animal model. Olive fruits are rich in dietary fibre and, overall, one of the most important compound is ferulic acid that has anti-inflammatory activity⁽ Reference Zhao, Suyama and Chumg ^{62 )}. Suntar et al. ⁽ Reference Suntar, Akkol and Baykal ^{63 )} have evaluated the anti-inflammatory and anti-nociceptive properties of leaves and fruits of Olea europaea L. (family Oleaceae) and the results revealed that ethanolic extract did not show a significant anti-inflammatory or analgesic activity, whereas the n-hexane extract displayed 12·7–27·8 % inhibition on the carrageenan-induced hind paw oedema model at the 400 mg/kg dose⁽ Reference Suntar, Akkol and Baykal ^{63 )}.

Online Supplementary Table S4 summarises the studies investigating the relationship between EVO intake and imbalance between antioxidant capacity, oxidative stress and pro/anti-inflammatory markers, which represent conditions present in chronic pain subjects.

In conclusion, the recommendation to all chronic pain subjects is daily EVO consumption, preferably raw, as a seasoning for food and a weekly consumption of olives (for example, to be added to salads).

Red meat, white meat and fish

An unbalanced diet that emphasises the consumption of food of animal origin at the expense of food of plant origin is associated with the development of chronic and degenerative diseases, which, in turn, are related to pain⁽ Reference Seaman ^{64 )}.

Components of the Mediterranean diet associated with better cardiovascular health include low consumption of meat and meat products⁽ Reference Shen, Wilmot and Ghasemzadeh ^{65 )}.

These foods may produce inflammatory molecules; higher red meat consumption is associated with unfavourable plasma concentrations of inflammatory and glucose metabolic biomarkers (such as IL-6) in diabetes-free women, and the substitution of other protein food, such as poultry, is associated with a healthier biomarker profile of inflammatory and glucose metabolism⁽ Reference Ozawa, Shipley and Kivimaki ^{66 )}.

Moreover, there is the impact of beefsteak thermal processing on lipid oxidation and postprandial inflammation-related responses: Nuora et al. ⁽ Reference Nuora, Chiang and Milan ^{67 )} evaluated the effect of the consumption of pan-fried and sous-vide steaks and it was shown that there were no postprandial differences in the plasma IL-6 and CRP levels. TNF-α levels after consuming the pan-fried meal remained at baseline throughout the monitoring period but there was a decrease in TNF-α levels after consuming the sous-vide meal.

Plasma monocyte chemotactic protein-1 (MCP-1) remained unaltered, relative to baseline values, after the pan-fried meal. In contrast, MCP-1 was reduced following the sous-vide meal⁽ Reference Nuora, Chiang and Milan ^{67 )}.

In order to obtain an adequate amount of protein if consuming animal products, we recommend consuming white meat twice per week, red/processed meat once per week, and fish four times per week.

Fish should contain larger amounts of n-3 PUFA, such as bluefish, mackerel, anchovies, sardines, tuna and swordfish, given the anti-inflammatory properties of these essential fatty acids: for example, the study of Maroon et al. ⁽ Reference Maroon and Bost ^{68 )}, in which individuals took a supplementation of n-3 essential fatty acids (EPA and DHA), found in fish oil supplements, demonstrated a reduction of pain⁽ Reference Maroon and Bost ^{68 ,} Reference Nakamoto, Nishinaka and Sato ^{69 )}.

Online Supplementary Table S5 summarises the studies showing the relationship between intake of red or white meat or fish and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, conditions present in chronic pain subjects.

In conclusion, excessive consumption of red meat causes an inflammatory state and alternative foods should be taken into consideration such as white meat and fish.

Legumes

Legumes are a pivotal component of the Mediterranean diet due to their beneficial effect on inflammatory markers.

In a recent cross-over study, subjects with type 2 diabetes were divided into two groups in order to analyse certain inflammatory markers as a result of two different types of 8-week diet intervention (identical isoenergetic diets, with the exception of two servings of meat replaced by two servings of vegetables). There was a significant decrease in CRP, IL-6 and TNF-α only during the period in which subjects took legumes compared with the period when they took meat, independent of weight change⁽ Reference Hosseinpour-Niazi, Mirmiran and Fallah-Ghohroudi ^{70 )}. These results were confirmed in a systematic review that involved eight studies and 464 participants, showing that the consumption of legumes (excluding soyabeans) had a significant effect on the reduction of CRP⁽ Reference Salehi-Abargouei, Saraf-Bank and Bellissimo ^{71 )}.

Regarding soyabeans, the literature reports that diets rich in soya create an anti-inflammatory effect through activation of the PPARγ receptor with consequent suppression of production of pro-inflammatory cytokines by immune cells⁽ Reference Martin ^{72 )}. Therefore, soya intake may be useful in controlling chronic pain, as reported by Shir et al. ⁽ Reference Shir, Raja and Weissman ^{73 )} in which rats were fed a soya or no-soya diet. With regard to studies on human subjects, Arjmandi et al. ⁽ Reference Arjmandi, Khalil and Lucas ^{74 )} showed a reduction in pain symptoms in patients with osteoarthritis taking a 3-month supplement of 40 g/d of soya proteins, as indicated by a significant increase in serum levels of insulin-like growth factor-1 and a significant decrease in serum levels of glycoprotein 39 (YKL-40) compared with a milk-based protein diet; specifically, the authors underline that major effects were observed in men rather than women, probably for higher levels of oestrogen in women as compared with men, because the effect of soya supplementation is related to its content of isoflavones⁽ Reference Arjmandi, Khalil and Lucas ^{74 )}.

The main soya isoflavone is genistein. It has been shown in in vitro studies that genistein binds to oestrogen receptors and activates PPAR-γ, which has a prominent role in the suppression of inflammatory genes. In cultured chondrocyte cells, put in contact with lipopolysaccharide, genistein reduces IL-1β expression, COX and NO, indicating a clear anti-inflammatory effect⁽ Reference Hooshmand, Soung do and Lucas ^{75 )}. The authors underline that there are no pharmaceutical agents that selectively can inhibit COX-2 production without having serious side effects. Therefore, genistein can be an attractive and viable alternative therapy for treatment or prevention of OA⁽ Reference Hooshmand, Soung do and Lucas ^{75 )}.

Finally, legumes are rich in water-insoluble fibre, and this feature makes them suitable for subjects suffering from opioid-induced constipation (OIC).

Online Supplementary Table S6 summarises the studies investigating the relationship between intake of legumes and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, conditions of chronic pain subjects.

In conclusion, it is recommended to consume legumes four times per week, either dried or fresh, and soyabean once per week for their anti-inflammatory activity and their high content of fibre.

Yogurt

Our body is an ideal habitat for the survival of bacterial strains. These micro-organisms are not always pathogenic; indeed, they often are an important defence and security barrier. The gut is the tract of the human body most colonised and overall resident bacteria form a complex and diverse ecosystem-defined microbiota. The alteration of the intestinal microbiota is a result of various conditions, such as prolonged use of antibiotics, changes in lifestyle, use of drugs, and diseases⁽ Reference Stecher ^{76 )}.

Under normal conditions, the intestinal microbiota is made from different bacterial strains belonging mainly to the genera Bacteroides, Eubacterium, Bifidobacterium, Fusobacterium, Peptostreptococcus and to a lesser extent Escherichia coli, Enterobacter and Lactobacillus, which produce a series of molecules able to activate both the innate and acquired immune systems, which may be altered in pathological conditions or during drug treatment⁽ Reference Harmsen, Raangs and He ^{77 )}.

It is therefore necessary that intestinal microbiota be adequately represented, in order to compete with the pathological bacteria that pass through the gastrointestinal tract, and in order to exert beneficial actions in different parts of the human body⁽ Reference Mayer, Knight and Mazmanian ^{78 )}.

Opioids, in particular morphine, are the main drugs that determine alteration of the innate and adaptive immunity of the patient, even though the mechanism of action is not fully known⁽ Reference Chang, Fan and Hsiao ^{79 )}. Specifically, opioids alter or suppress the function of pro-inflammatory cells (cytokines), through Toll-like receptors (TLR), while opioids in adaptive immunity act on B and T lymphocytes, respectively, through the hypothalamus–pituitary–adrenal axis, the molecules of histocompatibility class II (MHC II) and through the suppression of IL-2⁽ Reference Roy, Ninkovic and Banerjee ^{80 )}. A recent study using animal models showed that chronic use of morphine induces a significant change in the composition of the intestinal microbiota and determines an increase in Gram-positive pathogenic bacteria and a reduction in deconjugating bile strains. Moreover, this study also demonstrated that the Firmiculates:Bacterioidetes ratio, one of the key markers of inflammation in the microbiome, promotes the pro-inflammatory phenotype, demonstrating how the immune status of the host involves the innate immune response⁽ Reference Banerjee, Sindberg and Wang ^{81 )}.

Probiotics are defined by the FAO/WHO as ‘living organisms which bring benefit to the health of the host, when administered in adequate amounts’^{( 82 )}, while the literature defines prebiotics as a class of food products which constitute the necessary and optimum substrate for the growth and development of probiotics.

Among the prebiotics, inulin (contained in plants of the Lilliaceae family, such as leek, onion, garlic and asparagus, or of the Compositae family such as Jerusalem artichoke, dahlia and chicory), oligofructose and polyphenols have particular importance; they are metabolised by enteric bacteria⁽ Reference Bosscher, Breynaert and Pieters ^{83 )}.

Yogurt is the best-known substrate to which to add probiotics. Yogurt may be also be added to prebiotics (for example, fructo-oligosaccharides) that are useful in preventing alterations of the microbiota and to counteract constipation⁽ Reference Kapoor ^{84 )}, both critical situations induced by opioid therapy.

Yogurt intake is recommended in all pathologies characterised by an inflammatory state⁽ Reference Pei, Martin and Di Marco ^{85 )}. The intake of Bifidobacterium animalis subsp. lactis (BB-12) interacts with the peripheral myeloid cells via TLR-2, a receptor capable of recognising certain typical structures of pathogens and microbes, and it is implicated in the defence of the organism, in particular, of innate immunity⁽ Reference Meng, Ba and Lee ^{86 )}. Subjects who ingested yogurt with BB-12 probiotics had a lower expression of TLR-2 and thus a decrease in the triggering of the immune response as a result of inflammation. These results demonstrated a potential anti-inflammatory effect of BB-12 in healthy adults, and also indicated that the matrix to which the probiotics are added may influence the immunomodulatory properties.

Other authors conducted studies on the activity of probiotics on the immune system. Klein et al. ⁽ Reference Klein, Friedrich and Vogelsang ^{87 )} integrated yogurt with Lactobacillus acidophilus 74-2 and Bifidobacterium animalis subsp. lactis DGCC 420 (B. lactis 420) and demonstrated that the percentage of granulocytes and monocytes with phagocytic activity increased by 92–95 %, with a concomitant increase in L. acidophilus and B. lactis concentrations in faeces.

Probiotics (Lactobacillus bulgaricus and Streptococcus thermophilus, as well as other strains that may be added such as Lactobacillus acidophilus 74-2, Bifidobacterium animalis subsp. lactis DGCC 420, Bifidobacterium animalis subsp. lactis), and the protein content in yogurt, have an anti-inflammatory and immunomodulatory activity in human subjects, demonstrated by numerous intervention studies⁽ Reference Patel ^{88 )}.

Online Supplementary Table S7 summarises the studies investigating the relationship between intake of yogurt or fermented milk and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, conditions present in chronic pain subjects.

In conclusion, the daily intake of yogurt can prevent the alteration of the microbiota, a consequence of opioid therapy. It is also an excellent way to counteract the inflammatory state that characterises chronic pain patients.

Nuts and seeds and their oils

The use of seeds (nuts, such as walnuts, hazelnuts, almonds, and pistachios, pumpkin seeds, flax seeds, grapeseed) and oils derived from them for chronic pain treatment has been widely discussed in the literature. In animal models an extract of grape seeds may be useful as a natural treatment option for pain by suppressing the development of peripheral and central sensitisation, probably due to the high content of proanthocyanidins⁽ Reference Cady, Hirst and Durham ^{89 ,} Reference Woo, Joo and Jung ^{90 )}.

Walnuts are complex food matrices containing different macro- and micronutrients and other components that can influence inflammation and endothelial function. Examples of these components are essential fatty acids, n-3 PUFA, Mg, l-arginine and some antioxidants. Several intervention studies support the anti-inflammatory effect of ALA in human subjects. For example, there was a decrease in serum concentrations of inflammatory markers (CRP and vascular cell adhesion molecule-1 (VCAM-1)) after dietary supplementation with ALA⁽ Reference Zhao, Etherton and Martin ^{91 )}. The increased consumption of ALA from nuts is able to improve anti-inflammatory effects by inhibiting the peripheral production of IL-6, IL-1β and TNF-α⁽ Reference Zhao, Etherton and Martin ^{92 )}.

Moreover, walnuts are one of the main sources of Mg in the diet. Cross-sectional studies have suggested an inverse association between Mg intake and the concentrations of CRP⁽ Reference Song, Ridker and Manson ^{93 )}. Some lines of experimental evidence have also suggested that Mg intake may have beneficial effects on endothelial function⁽ Reference Shechter, Sharir and Labrador ^{94 )}, probably mediated by the effects of this mineral on systemic inflammation. As regards arginine, a conditionally essential amino acid contained in high amounts in walnuts (3·62 g in 100 g), it could have a positive effect on endothelium-dependent vasodilatation⁽ Reference Ros, Núñez and Pérez-Heras ^{95 )}; however, endothelium-independent vasodilation and levels of intercellular adhesion molecule-1, CRP, homocysteine and oxidation biomarkers were similar after each diet (a Mediterranean diet and a diet in which walnuts replaced about 32 % of the energy from monounsaturated fat)⁽ Reference Ros, Núñez and Pérez-Heras ^{95 )}. A cross-sectional study evaluated the association between the intake of arginine and CRP, demonstrating that individuals with higher intakes of arginine had 30 % less probability of having a CRP of more than 3·0 mg/l. All studies led to the conclusion that the consumption of foods rich in arginine, such as nuts, can reduce the risk of diseases characterised by the presence of inflammation⁽ Reference Wells, Mainous and Everett ^{96 )}.

Pistachio is another seed with significant anti-inflammatory activity. It is particularly rich in γ-tocopherol, vitamin K, phytosterols, carotenoids, some minerals (Cu, Fe and Mg) and B vitamins⁽ Reference Bulló, Juanola-Falgarona and Hernández-Alonso ^{97 )}. A diet rich in pistachios (pistachio was added for 4 weeks by replacing the monounsaturated fat content constituting about 20 % of daily energy intake) significantly improves endothelium-dependent vasodilatation (+30 %), contributes to a decrease in serum IL-6, total oxidant status, lipid hydroperoxide, and malondialdehyde, and leads to an increase in superoxide dismutase, with a significant change in TNF-α levels and CRP⁽ Reference Sari, Baltaci and Bagci ^{98 )}.

Flax seeds, rich in ALA, are also known for their anti-inflammatory effect: Faintuch et al. ⁽ Reference Faintuch, Horie and Barbeiro ^{99 )} showed a decrease in CRP values, serum amyloid A, leucocytes and fibronectin in a group of obese patients, supplemented with 30 g/d of flax flour.

Pumpkin seeds have several beneficial effects on health, including antioxidant and anti-inflammatory properties. They have a high content of vitamin E (tocopherol)⁽ Reference Imaeda, Tokudome and Ikeda ^{100 )}. Chang⁽ Reference Chang ^{101 )} found that the administration of pumpkin extract can significantly increase the blood and hepatic activity of superoxide dismutase and glutathione peroxidase in mice, as well as the concentration of malonaldehyde.

Pumpkin seeds are considered a good source of anti-inflammatory substances, which can help in many diseases, such as arthritis. Pumpkin seed oil can significantly inhibit arthritis in mice, with an action similar to indomethacin⁽ Reference Fahim, Abd-el Fattah and Agha ^{102 )}.

Online Supplementary Table S8 summarises the studies about the relationship between intake of oilseeds and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, conditions present in chronic pain subjects.

In conclusion, the intake of 30 g/d of oilseeds (particularly walnuts and pistachios) can be a suitable nutritional option to counterbalance the pro-inflammatory activity in chronic pain patients.

Spices

It is clear that the Mediterranean diet has an important anti-inflammatory role, probably affecting the arachidonic acid cascade, the expression of some proinflammatory genes, and the activity of immune cells⁽ Reference Oliviero, Spinella and Fiocco ^{103 )}. The adoption of this dietary pattern could counter the effects of several inflammatory markers, decreasing, for example, the secretion of circulating and cellular biomarkers involved in the atherosclerotic process⁽ Reference Casas, Sacanella and Estruch ^{104 )}.

Daily consumption of spices is often recommended because they are useful for flavouring dishes without using excessive amounts of salt, but spices have many other positive health properties. The extracts of plants belonging to the Zingiberaceae family (for example, turmeric, ginger, Javanese and galangal ginger) are powerful ipoalgesic agents, useful in chronic pain treatment⁽ Reference Lakhan, Ford and Tepper ^{105 )}. Specifically, curcumin (obtained from Curcuma longa) attenuates hyperalgesia induced by opioids, one of the main chronic pain treatments, possibly by inhibiting CaMKIIα (Ca/calmodulin-dependent protein kinase type II alpha chain) and its downstream signalling⁽ Reference Hu, Huang and Szymusiak ^{106 )}. In addition, curcumin has antinociceptive and anti-inflammatory effects⁽ Reference Salas, Cheppudira and Fowler ^{107 )}.

Treatments with herbal preparations (including Zingiber officinale) are useful in reducing chronic joint pain⁽ Reference Chopra, Saluja and Tillu ^{108 )}. Gingerols and shogaols, found in Zingiber officinale, have an analgesic effect as they are agonists of the transient receptor potential (TRP) cation channel subfamily V1 (TRPV1), showing inhibitory activity on the metabolism of arachidonic acid through COX2 (PG and thromboxanes)⁽ Reference Vriens, Nilius and Vennekens ^{109 ,} Reference Semwal, Semwal and Combrinck ^{110 )}.

In addition, gingerols also exert analgesic effects through the activation of vanilloid receptor subtype-1 (VR1); the potency of gingerols increases with increasing size of the side chain and with the overall hydrophobicity in the series⁽ Reference Dedov, Tran and Duke ^{111 )}. Finally, a particularly volatile compound present in many spices (such as oregano, cinnamon, rosemary, thyme and black pepper), named β-caryophyllene, is a selective agonist of the peripheral cannabinoid receptor type 2 (CB2), involved in modulating inflammation, especially in neuropathic pain, by reducing pain and neuro-inflammation in animal models⁽ Reference Klauke, Racz and Pradier ^{112 )}.

Online Supplementary Table S9 summarises studies investigating the relationship between spice intake and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, conditions of chronic pain subjects.

In conclusion, the daily use of spices, especially turmeric and ginger, could have a significant positive activity on chronic pain control due to their antinociceptive and anti-inflammatory actions.

Eggs

Eggs contain particularly beneficial substances, such as fat-soluble and B vitamins, minerals, choline and carotenoids, high-quality proteins, and bioactive components with both pro- and anti-inflammatory roles that contribute to fighting inflammation in human populations.

Phospholipids (for example, phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, phosphatidylinositol and sphingomyelin), mostly found in the yolk, are an example of this dual role: although the evidence suggests that phosphatidylcholine has anti-inflammatory effects⁽ Reference Treede, Braun and Sparla ^{113 ,} Reference Treede, Braun and Jeliaskova ^{114 )}. Through the role of TNF-α, phospholipids are also involved in inflammatory and atherosclerosis processes through the formation of trimethylamine-N-oxide, which promotes the formation of atherosclerotic plaques⁽ Reference Andersen ^{115 )}.

For this reason, in addition to the known higher cholesterol content, it is recommended to limit egg intake to twice per week. Eggs also contain lutein and zeaxanthin (belonging to the family of carotenoids) with antioxidant and anti-inflammatory properties, whose bioavailability is greater than in vegetable foods. Notably, normal-weight individuals have greater pro-inflammatory responses to egg intake than overweight individuals with the metabolic syndrome, or type 2 diabetes⁽ Reference Klauke, Racz and Pradier ^{112 )}. A recent study highlighted the ability of eggs (one egg per d) to decrease TNF-α in populations with a low degree of chronic inflammation⁽ Reference Ballesteros, Valenzuela and Robles ^{116 )}.

Online Supplementary Table S10 summarises studies about the relationship between intake of eggs and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, conditions of chronic pain subjects.

Cheeses

It is known that dairy products (milk, yogurt and cheese) exert important functions in the human body thanks to the content of high-quality proteins, Ca and vitamins, in particular vitamin D, and for this reason they should be taken daily. Cheeses are divided into fresh and mature: the first include ricotta, mozzarella, first salt, and cottage cheese. Among the latter, examples are Parmesan, fontina, provolone and scamorza. Experimental and epidemiological studies have shown that regular intake of dairy products has inhibitory effects against the development of some chronic degenerative diseases, characterised by low levels of inflammation, such as the metabolic syndrome⁽ Reference Drehmer, Pereira and Schmidt ^{117 )}.

Moreover, some cheeses contain whey protein, quickly absorbed by the human body, with antioxidant properties⁽ Reference Bounous, Batist and Gold ^{118 )}. Whey protein may exert its effect by enhancing glutathione concentration⁽ Reference Bounous, Batist and Gold ^{118 )}.

Schmidt et al. ⁽ Reference Schmidt, Petry and Walther ^{119 )} compared the effect of a high-fat dairy meal, a high-fat non-dairy meal supplemented with milk and a high-fat non-dairy control meal on postprandial inflammatory and metabolic responses in healthy men: they suggested that full-fat milk and dairy products have no significant impact on the inflammatory response to a high-fat meal⁽ Reference Schmidt, Petry and Walther ^{119 )}.

Demmer et al. ⁽ Reference Demmer, Van Loan and Rivera ^{120 )} performed a randomised controlled cross-over trial and compared the intake of saturated fat in the form of cheese compared with plant sources of saturated fat; the results of this study demonstrated that postprandial CRP was significantly lower in response to the cheese compared with the vegan test meal⁽ Reference Demmer, Van Loan and Rivera ^{120 )}.

The 6-week cross-over study by Dugan et al. ⁽ Reference Dugan, Aguilar and Park ^{121 )}, which compared inflammatory responses (IL-6, IL-1β, TNF-α and MCP-1) as a result of diet with low-fat dairy (10 oz (283 g) 1 % milk, 6 oz (170 g) non-fat yogurt, 4 oz (113 g) 2 % cheese) or with low-fat non-dairy intake (carbohydrate-based control: 1·5 oz (43 g) granola bar and 12 oz (340 g) 100 % juice), demonstrated in patients with the metabolic syndrome that three dairy product servings per d of low-fat dairy food improved systemic inflammation⁽ Reference Dugan, Aguilar and Park ^{121 )}.

The same positive results have been demonstrated by Bordoni et al. ⁽ Reference Bordoni, Danesi and Dardevet ^{122 )} who carried out a systematic review of fifty-two clinical trials investigating inflammatory markers in relation to the consumption of dairy products. However, in this review there are important limitations; in particular no distinction is made between cheeses with a lower content of saturated fat and cheeses with a high content of saturated fat and cholesterol; in fact, it is well known that excessive intake of saturated fat and cholesterol can cause increased levels of inflammation. Recently, Rocha et al. ⁽ Reference Rocha, Caldas and Oliveira ^{123 )} provided a new perspective on the potential mechanism by which SFA could modulate TLR4-induced inflammatory responses. However, now even this topic is heavily debated in the literature because the results do not all agree. Van Meji & Mensink⁽ Reference Van Meji and Mensink ^{124 )} carried out a comparative study on the inflammation response in which thirty-five overweight subjects consumed, in a random order, low-fat dairy products (500 ml low-fat milk and 150 g low-fat yogurt) or carbohydrate-rich control products (600 ml fruit juice and three fruit biscuits) daily for 8 weeks. The results of this study indicated that in overweight subjects, low-fat dairy product consumption, compared with carbohydrate-rich product consumption, may modulate TNF-α signalling by increasing soluble TNF receptor-2, but that it does not affect other markers of low-grade systemic inflammation and endothelial function in overweight subjects⁽ Reference Van Meji and Mensink ^{124 )}.

Online Supplementary Table 11 summarises studies that investigate the relationship between intake of cheeses and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, all conditions present in chronic pain subjects.

In conclusion, the intake of cheeses, in particular with a high content of whey protein, is recommended at least twice per week.

Red wine

The consumption of moderate doses of wine (one glass of 125 ml/d for women and two glasses for men) is useful in the prevention of many inflammatory diseases, probably by activating sirtuin-1 (SIRT1)⁽ Reference Giacosa, Barale and Bavaresco ^{125 ,} Reference Giacosa, Adam-Blondon and Baer-Sinnott ^{126 )}.

Red wine is rich in numerous active molecules against inflammation and oxidative stress (in particular flavonoids, such as quercetin and myricetin, catechin and epicatechin, proanthocyanidins, anthocyanidins and the stilbene resveratrol). These molecules determine an increased expression of nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1, a protein capable of deacetyl nuclear and cytoplasmic proteins controlling critical cellular processes, such as apoptosis and metabolism. SIRT1 regulates the production of insulin and glucose, lipids and cell survival⁽ Reference Kida and Goligorsky ^{127 )}.

Flavonoids have a significant positive effect on immune system functions and on inflammatory cells, as demonstrated in numerous in vitro and animal model studies⁽ Reference Middleton and Kandaswami ^{128 ,} Reference Middleton ^{129 )}. Flavonoids are able to inhibit the expression of isoforms of NO synthase, COX and lipoxygenase, which are responsible for the production of a large amount of NO, prostanoids, leukotrienes, and other mediators of the inflammation process such as cytokines, chemokines and adhesion molecules⁽ Reference Tunon, Garcia-Mediavilla and Sanchez-Campos ^{130 )}. The flavonoids also inhibit phosphodiesterase involved in cell activation. Many anti-inflammatory effects of the flavonoids affect the biosynthesis of cytokines that mediate adhesion of circulating leucocytes to sites of injury. Some flavonoids are potent inhibitors of the production of PG, a group of powerful pro-inflammatory signalling molecules⁽ Reference Manthey ^{131 )}.

As regards resveratrol, recent studies have shown that it modulates neuronal excitability in the nervous system, both central and peripheral channels through the TRP ion channels and voltage-dependent channels⁽ Reference Grannados-Soto, Argulles and Ortiz ^{132 –} Reference Yu, Wang and Kogure ^{136 )}.

For example, TRP ankyrin 1 (TRPA1) modulates the mechanical transduction in primary sensory neurons⁽ Reference Kwan, Glazer and Corey ^{137 )}, and it has been shown that resveratrol is a potent inhibitor of TRPV1 in vitro and in vivo ⁽ Reference Yu, Wang and Kogure ^{136 )}, suggesting that resveratrol attenuates the generator potential via the mechanical transduction process. In addition, resveratrol modulates the channels of Na and K in the dorsal root ganglia neurons that are associated with the generation of action potentials⁽ Reference Grannados-Soto, Argulles and Ortiz ^{132 ,} Reference Kim, Kim and Song ^{133 )}. On the contrary, in the hippocampus, resveratrol significantly suppresses glutamate-induced currents in CA1 pyramidal postsynaptic neurons⁽ Reference Gao, Chen and Hu ^{138 )} that contribute to excitatory synaptic transmission. In addition, literature data show that resveratrol decreases the duration of the action potential and L-type Ca²⁺ currents in excitable tissues⁽ Reference Liew, Stagg and MacLeod ^{134 )}. Together, these results suggest that systemic administration of resveratrol may suppress sensory transmission, including nociception, in both the central and peripheral nervous system, as demonstrated in a recent animal model study, in which the acute intravenous administration of resveratrol suppressed trigeminal nociceptive transmission⁽ Reference Takehana, Sekiguchi and Inoue ^{139 )}.

Online Supplementary Table S12 summarises the studies about the relationship between red wine intake and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, present in chronic pain subjects.

In conclusion, the numerous molecules active against inflammation and oxidation of red wine determine increased expression levels of SIRT1. Resveratrol modulates neuronal excitability. It is recommended to consume one 125 ml glass/d for women and two glasses for men to control pain in chronic pain patients without continuous opioid and/or benzodiazepine drug treatments; a greater amount should be avoided because of the risk of addiction/abuse.

Alcohol consumption and opioids

The association between alcohol and opioid analgesics may result in ‘dose dumping’. This is defined as the unintended quick release (in a short period of time) of the total amount (or a significant fraction) of the drug in a dosage form with modified release.

Alcohol is related to dose-dumping in all long-acting specific opioid formulations (LAO), and it significantly increases their side effects⁽ Reference Fields ^{140 )}. Therefore, it has been recommended that patients not drink alcohol during treatment, because they may have ‘the rapid release and absorption of a potential fatal dose of opioids’⁽ Reference Carson, Thakurta and Low ^{141 )}.

The mechanism by which alcohol alters the pharmacokinetic properties of LAO are little known. Several studies have shown that the concomitant use of alcohol increases the maximum plasma concentration (C_max) of some opioids and decreases the time to C_max (T_max), despite no evidence of dose dumping⁽ Reference Fiske, Jobes and Xiang ^{142 –} Reference Johnson, Ciric and Boudriau ^{144 )}. Specifically, Fiske et al. ⁽ Reference Fiske, Jobes and Xiang ^{142 )} demonstrated that increased systemic exposure to oxymorphone was greatest in the presence of excessive levels of ethanol (40 %), which models serious ethanol abuse, but its clinical importance is not known.

These observations underscore the importance of educating patients not to consume alcoholic beverages while taking LAO therapies. Fatal poisonings involving pharmacological opiates are often associated with the use of alcohol and are probably due to a combination of effects on the central nervous system and of the respiratory tract⁽ Reference Hakkinen, Launiainen and Vuori ^{145 ,} Reference Webster, Cochella and Dasgupta ^{146 )}.

Ali et al. ⁽ Reference Ali, Marshall and Allen ^{147 )} showed that opioids have a significantly decreased ventilatory response to hypercapnia when administered together with ethanol. About 12 % of patients under chronic opioid treatment consume ethanol⁽ Reference Saunders, Von Korff and Campbell ^{148 )}, and therefore physicians must take into consideration the possible development of adverse events⁽ Reference Wenghofer, Wilson and Kahan ^{149 )}.

In conclusion, given the prevalence of concomitant use of opioids and ethanol and the potential risks to health (respiratory depression and sedation) associated with simultaneous administration⁽ Reference Weathermon and Crabb ^{150 )}, it is important to implement information on safety, pharmacokinetics and pharmacodynamics following concurrent administration of alcohol and opioids.

Homemade sweets

The consumption of sweets is placed at the top of the pyramid, signifying that their intake should be occasional (maximum once per week). As described in the chapter on cereal consumption, the intake of high-glycaemic index foods (and sweets are foods with a high glycaemic index) can contribute to greater oxidative stress and create a state of low-grade chronic inflammation⁽ Reference Dickinson, Hancock and Petocz ^{35 )}.

The intake of a Western-style diet (with high amounts of simple sugars and sweets) causes an increase in inflammatory markers⁽ Reference Defagó, Elorriaga and Irazola ^{151 )}, such as CRP, IL-6, E-selectin, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), after adjustment for all confounding factors⁽ Reference Lopez-Garcia, Schulze and Fung ^{152 ,} Reference Nettleton, Steffen and Mayer-Davis ^{153 )}.

Nevertheless, we should not underestimate the positive effect of dark chocolate (minimum 70 % of cocoa solids) that is able to reduce NO production and then oxidative stress thanks to its flavonoid content⁽ Reference Katz, Doughty and Ali ^{154 )}. Regular consumption of dark chocolate determines the reduction in inflammation, evaluated by CRP⁽ Reference di Giuseppe, Di Castelnuovo and Centritto ^{155 )}.

Online Supplementary Table S13 summarises studies investigating the relationship between intake of sweets and imbalance between antioxidant capacity and oxidative stress and pro/anti-inflammatory markers, conditions present in chronic pain subjects.

In conclusion, it is right to enjoy the satisfaction of consuming a sweet, but homemade preparations are preferred, based on wholemeal flour with a lower glycaemic index than a refined one, and dark chocolate (70 % cocoa).

Dietary supplements

On top of the food pyramid for the dietary management of chronic pain there is a pennant, to remind us that chronic pain subjects require special dietary supplements: vitamin D, vitamin B₁₂, micronutrients (Zn and Se), fibre and n-3 fatty acids.

Role of dietary fibre in opioid-induced constipation

The most current diagnostic criteria of constipation have been developed during the Rome III Consensus Conference⁽ Reference Longstreth, Thompson and Chey ^{172 )}:

1. (1) At least two or more of the following characteristics in at least 25 % of the discharges: effort in defecation of hard stools; sensation of incomplete evacuation; feeling of occlusion; less than three defecations per week; need for manual manoeuvre to evacuate.

2. (2) Rare evacuations without resorting to laxatives.

3. (3) Exclusion from the diagnosis of irritable bowel syndrome.

Presence of other symptoms, such as bloating or abdominal distension, may be present, but they are not the symptomatic elements. The pathological mechanism, which causes the OIC, is due to the effect of these drugs on peripheral μ-receptors in the gut wall⁽ Reference Reimer, Hopp and Zenz ^{173 )}. The μ-opioid receptors are present in the neurons of the myenteric plexus and submucosal and immune cells of the lamina propria⁽ Reference Davis ^{174 )}. The activation of μ-opioid receptor inhibits neuronal excitatory and inhibitory pathways in the enteric nervous system, which coordinates motility.

The inhibition of excitatory neuronal pathways decreases peristaltic contractions; the blockade of inhibitory neuronal processes increases the muscular activity of the gastrointestinal tract and elevates the resting muscle tone with the consequence of inducing spasm. These mechanisms lead to a delay in gastric emptying and slow intestinal transit⁽ Reference Holzer ^{175 )}.

The opioid drugs in cancer patients increase the use of treatment for constipation, with a predominance of monotherapy⁽ Reference Trinkley, Sill and Porter ^{176 )}. Patients using opioids, suffering from OIC, incur a greater number of adverse effects, which result in increased use of medical care, thereby raising the cost of health care. Patients with opioid-related adverse drug events have a great risk for hospitalisation, ranging from 10·3 to 55 %.

Estimates of OIC have been found to vary widely, with investigations identifying rates of OIC among opioid users ranging from 15 to 90 %⁽ Reference Ledade, Jain and Darji ^{18 ,} Reference Wan, Corman and Gao ^{177 –} Reference Jones, Prommer and Backstedt ^{179 )}, resulting in an increase in care costs from 7·4 to 47 %⁽ Reference Kane-Gill, Rubin and Smithburger ^{180 )}.

Improving the management of constipation can lead to an optimisation of drug therapy and prevents the interruption of opioid drugs already in use. This interruption would lead to deterioration in the quality of life, which in turn would lead the patient to new access to medical care, with recovery therapy with multiple drugs and associated increased costs⁽ Reference Candrilli, Davis and Iyer ^{181 )}.

About 10 % of emergency room visits have a diagnosis of constipation. Furthermore, constipation was reported to be one of four factors that significantly and independently predict hospitalisation in hospice care⁽ Reference Addington-Hall, Altmann and McCarthy ^{182 )}. Several studies in patients with advanced cancer receiving hospice care in fact showed that the prevalence of constipation is between 23 and 84 %⁽ Reference McMillan and Tittle ^{183 –} Reference Weitzner, Moody and McMillan ^{189 )}. In addition, a series of studies conducted in a large hospice in Florida evaluated OIC, demonstrating that it occurs in 40–64 % of hospitalised cancer patients. However, the number was found to be lower when the data were obtained from a screening of staff (40 %) and higher when the researchers interviewed patients about their symptoms (63–64 %)⁽ Reference Weitzner, Moody and McMillan ^{189 –} Reference McMillan and Weitzner ^{191 )}.

Moreover, it is important to note that possible associations have been hypothesised between the impairment of intestinal integrity and musculoskeletal chronic pain, like fibromyalgia and chronic myofascial pain, emphasising the synthesis and release of proinflammatory cytokines in these clinical situations⁽ Reference Barros-Neto, Souza-Machado and Kraychete ^{192 )}.

In conclusion, counteracting constipation is an important point in the management of patients with opioid-related adverse drug events, as various studies have shown that the presence of constipation is significantly negatively correlated to the overall quality of life⁽ Reference McMillan and Small ^{193 –} Reference Stannard ^{196 )}.

Multidisciplinary patient management, including analysis of life-style, should be performed at the beginning of opioid therapy and continue for the duration of the treatment; typical measures should include consumption of dietary fibre, fluid and increased physical activity⁽ Reference Kurz and Sessler ^{197 )}.

In ambulatory cancer patients with drug-induced constipation, an increase in fibre consumption should be recommended up to 30–35 g/d⁽ Reference Portenoy and Derby ^{198 )}, according to specific protocols⁽ Reference Robinson, Fritch and Hullett ^{199 –} Reference Mounsey, Raleigh and Wilson ^{200 )}. Animal model studies confirm that fibre can be a preventive factor for OIC. Moreover, the presence of SCFA products from the microbiota improve intestinal transit, promoting colon motility⁽ Reference Niwa, Nakao and Hoshi ^{201 )}. The use of prebiotics could further help, improving immunity in the intestine, increasing IgA and acting on oxidative stress, positively affecting intestinal peristalsis⁽ Reference Li, Zong and Qi ^{202 )}.

OIC improvement may also occur thanks to non-pharmacological management. Cancer patients should be encouraged to eat more high-fibre foods, such as fruits (plums, peaches and apples), vegetables (squash, broccoli, carrots and celery) and whole grains, and to increase fluid intake^{( 203 )}.

Online Supplementary Table S18 summarises the studies about the relationship between intake of supplementation of fibre and constipation, conditions present in patients with opioid-related adverse drug events.

In conclusion, a targeted diet, rich in fibre (35 g/d, in a ratio of 3:1 between insoluble and soluble fibre with an adequate intake of water) and with five meals daily, can be helpful in preventing and solving problems related to the assumption of drugs used to combat chronic pain, such as OIC.