The emergence of new data suggests that the benefits of Vitamin D extend beyond healthy bones. This paper looks at Vitamin D and its role in the aetiology and maintenance of chronic pain states and associated comorbidities. The interfaces between pain and Vitamin D and the mechanisms of action of Vitamin D on pain processes are explored. Finally the association between Vitamin D and pain comorbidities such as sleep and depression is investigated. The paper shows that Vitamin D exerts anatomic, hormonal, neurological, and immunological influences on pain manifestation, thereby playing a role in the aetiology and maintenance of chronic pain states and associated comorbidities. More research is necessary to determine whether Vitamin D is useful in the treatment of various pain conditions and whether or not the effect is limited to patients who are deficient in Vitamin D.
A recent surge of published data on the proven or potential effects of Vitamin D has raised much interest in the medical community. The primary role of Vitamin D is the regulation of serum calcium levels within a narrow range. Vitamin D plays an essential role in bone formation, maintenance, and remodelling, as well as in muscle function. However, the emergence of new data suggests that the benefits of Vitamin D extend beyond healthy bones. Of great interest is the role it could play in optimising neuromuscular functioning, reducing inflammation, and decreasing the risk of many chronic illnesses; these include a variety of cancers, autoimmune diseases, infectious diseases, and cardiovascular diseases [1–5]. Research has shown that Vitamin D exerts anatomic, hormonal, neurological, and immunological influences on pain manifestation, thereby playing a role in the aetiology and maintenance of chronic pain states and associated comorbidity [1, 6–8].
2. Vitamin D
2.1. Synthesis, Absorption, and Metabolism of Vitamin D
Chemically, Vitamin D is a fat soluble secosteroid (i.e., a steroid in which one of the bonds in the steroid rings is broken). There are various forms of Vitamin D; the most common forms are Vitamin D3(cholecalciferol) and Vitamin D2 (ergocalciferol). Both are collectively known as calciferol. Although it is called a vitamin, Vitamin D is really a hormone as it can be produced endogenously by humans. In the skin, 7-dehydrocholesterol is converted to pre-Vitamin D3 by a narrow band of solar ultraviolet radiation (290–320 nm) that undergoes isomerisation in a temperature-dependent manner to Vitamin D3. Ten thousand to 20,000 IU of Vitamin D can be produced in 30 minutes of whole-body exposure to sunlight. This endogenously produced Vitamin D enters the blood and binds with Vitamin D binding protein (DBP), facilitating transportation to the liver [1, 5]. Vitamin D can also be obtained from a limited number of dietary sources. Vitamin D2 (ergocalciferol) is produced by some kinds of plants and animals when ergosterol is altered by ultraviolet irradiation. However, few foods have naturally occurring substantial Vitamin D2 levels to make this a significant source of Vitamin D in humans.
Vitamin D from the skin and diet is hydroxylated in the liver by one of several cytochrome P450 enzymes to the prehormone 25-hydroxy Vitamin D [calcidiol, or 25(OH)D] that is encoded by the gene CYP27A1 [2, 5, 9]. Most circulating 25(OH)D and the active form of Vitamin D, namely, 1,25-dihydroxyvitamin D [1,25(OH)2D], are transported in the blood bound to Vitamin D binding protein (DBP) (80–90%) and to albumin (10–20%); only a small fraction remains free or unbound . The 25(OH)D can be taken up by one of two mechanisms, namely, diffusion of free 25(OH)D across cell membranes throughout the body or a DBP receptor mediated endocytosis by the coreceptors megalin and cubulin . It appears that endocytic transportation may be influenced by certain pathological and physiological determinants [11–13]. The amount of DBP and its effect on free versus bound 25(OH)D could inversely influence the available free 25(OH)D for uptake . The primary determinant of how long a Vitamin D metabolite will stay in circulation is its affinity for DBP . Further research is needed to understand the regulation of mobilization of 25(OH)D from lipid storage pools relative to health outcomes.
However, Vitamin D can also be hydroxylated to 25(OH)D in all tissues of the body, achieving autocrine production of 25(OH)D in these tissues . 25(OH)D is then further metabolised in the kidneys and possibly in a wide variety of extrarenal tissues by the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) to its active form, namely, 1,25-dihydroxyvitamin D [1,25(OH)2D3]. Vitamin D exerts its effects by modulating gene expression after binding to VDR. There appear to be potential genetic polymorphisms in key genes with Vitamin D exposure that can influence bioavailability, transport, and distribution in lipid storage pools, metabolism, and action of Vitamin D .
Pain is part of the human condition. Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described by the patient in terms of such damage” . Pain is essentially a subjective perceptual experience. Pain originates in the nociceptors of the nervous system but the experience of pain is perceived in the conscious brain. It is influenced by a complex interaction of behavioural, environmental, biological, and societal factors.
There are two broad categories of pain, namely, acute nociceptive pain which acts as an early warning sign and pathological persistent pain, which is essentially an ongoing false alarm [16, 17].
Acute pain is a sensation that is elicited after strong stimulation of tissues in the body. Nociception relates to the biochemical and neural changes that occur in response to a noxious stimulus . This stimulation causes action potentials in primary sensory neurones known as nociceptors. These nociceptors are activated by high-threshold stimuli (mechanical, thermal, chemical, or electrical) to transmit excitatory signals to the sensory cell bodies in the dorsal root ganglion (DRG) along the dorsal roots and subsequently into the spinal cord [16, 19]. In the spinal cord, these primary sensory nerve fibres release neurotransmitters such as amino acids (glutamate) and neuropeptides (such as substance P and calcitonin gene related peptide) that activate second-order neurones. The second-order neurones relay information via specific tracts that reach the thalamus where the sensation of pain occurs. Third-order neurones connecting the thalamus to the somatosensory cortex are activated, resulting in the perception of pain [16, 20].
Nociceptors are present in most tissues in the body, including skin, muscle, joints, and viscera. There are predominantly two types of nociceptors involved in the pain pathway, namely, C fibres and A-delta fibres. The thin, myelinated A-delta fibres are fast transmitting; they are activated by both mechanical and thermal stimuli . The unmyelinated C fibres respond to chemical, thermal, and mechanical stimuli. C fibres in the viscera are notable in that they respond to noxious stimuli such as the stretching of hollow organs.
The International Association for the Study of Pain (IASP) defines chronic pain as “pain that has persisted beyond normal tissue healing time.” This is taken (in absence of other criteria) to be 3 months . However, some chronic pain disorders are characterised by recurrent short acute episodes and exacerbations such as trigeminal neuralgia and rheumatoid arthritis.
Chronic pain can be produced after tissue damage (or inflammation), after nerve damage, and after alteration of normal neural function. Chronic persistent pain leads to chemical, functional, and anatomical changes throughout the nervous system (in the periphery, spinal cord, and brain) [22–24]. The concept of neuroplasticity (the ability of the brain to change its structure and function) can be a positive adaptation to loss of function; in the case of pain, it appears maladaptive . Persistent pain alters the nervous system to produce spontaneous pain that arises without any apparent peripheral stimulus as well as a hypersensitivity to peripheral stimuli [16, 17, 26]. Pain hypersensitivity can result in hyperalgesia (the exaggerated and prolonged response to noxious stimulation) and allodynia (pain resulting from a stimulus that is normally nonpainful) . The reduced descending inhibition in the central nervous system (CNS) results in more peripheral noxious signals getting through to the brain resulting in an increased experience of pain .
The transition from acute to chronic pain is not well understood and appears to be multifactorial . Nociceptive pain usually (but not always) reduces with healing. While persistent pain is often due to obvious nerve damage (e.g., injury or cancer), there are many instances when no physical pathology can be objectively verified, such as in fibromyalgia syndrome and in headaches. In general, chronic pain may involve a combination of nociceptive and neuropathic mechanisms, as well as some form of central sensitization and learnt response. The concept of central sensitization is becoming more widely recognised, whereby changes occurring within the nervous system result in previously nonnoxious stimuli being perceived as painful, a lowering of the threshold for pain generation, and an increase in the duration, amplitude, and spatial distribution of pain . In addition, central sensitization initiates the interrelationship between many pain problems such as fibromyalgia, irritable bowel, low back pain, and chronic daily headache . Inflammatory and nerve injury are involved in the aetiology of many chronic pain syndromes like osteoarthritis, diabetic neuropathy, or postherpetic neuralgia, but only a small proportion of those subjected to such injuries actually develop chronic pain, and the degree of pain severity can vary significantly between patients .
Evidence from large scale studies in Europe, North America, and Australasia has shown that about one in five of the adult population experiences chronic moderate to severe pain with other estimates indicating the prevalence of chronic pain to be closer to 20–25% [32–34]. The incidence of chronic pain can be higher in at-risk groups such as the elderly and the immune-compromised [35, 36]. The rate of persistent severe pain among all residents of United States nursing homes in 1999 was found to be 14.7%, with 41.2% of residents in pain at first assessment experiencing severe pain 60 to 180 days later .
The prevalence of chronic pain is projected to increase as the population ages (from around 3.2 million Australians in 2007 to 5.0 million by 2050) . Life-style changes leading to obesity and inactivity will also contribute to increased level of pain in developed countries.
4. Interfaces of Pain and Vitamin D
Clinical research in the area of chronic pain and Vitamin D deficiency remains limited. There is a dearth of large double blind randomised controlled studies. However, there is enough evidence showing the potential of Vitamin D to exert anatomic and physiological influences on pain manifestation, thereby playing a role in the aetiology and maintenance of chronic pain states and associated comorbidity [1, 6]. Persistent pain is associated with Vitamin D-related bone demineralization, myopathy, and musculoskeletal pain. Pain pathways associated with cortical, immunological, hormonal, and neuronal changes are potentially also influenced by Vitamin D levels.
Vitamin D levels have been found to be low in certain groups of patients with various pain states (Box 1) [39–43]. Studies of Vitamin D supplementation in patients with known Vitamin D deficiency have shown mixed results in chronic pain patients regarding improved pain scores (Box 1) [6, 9, 44–51]. The prevalence of a variety of pain states at particular latitudes has been linked to low levels of Vitamin D [52–54]. Seasonal variations correspond with varying pain levels as well . Vitamin D deficiency has been associated with headache, abdominal, knee, and back pain, persistent musculoskeletal pain, costochondritic chest pain, and failed back syndrome and with fibromyalgia [6, 45, 53–59].