Concept:Vitamin B6 Pyridoxine and TrPs

Vitamin B₆ (pyridoxine) is considered the single most important vitamin in myofascial pain syndrome (MPS) because of its role in energy metabolism, in nerve function, and critically in the synthesis and/or metabolism of nearly all the neurotransmitters. It is also essential to the metabolism of many proteins, including several neurotransmitters. Pyridoxine deficiency is almost never found alone — it usually occurs with deficiency of other B-complex vitamins and interacts with nearly every other nutrient of relevance to myofascial pain.

Discovery and History

In 1934, Szent-Györgyi identified a dietary factor that prevents rat acrodynia — a dermatitis of the tail, ears, mouth and paws characterised by oedema and scaliness of the skin. He later named this substance vitamin B₆. Vitamin B₆ is a complex formed from three distinct, chemically different compounds: pyridoxal (an alcohol), pyridoxal (an aldehyde), and pyridoxamine (an amine). These are the dietary precursors of the active coenzyme forms. The precursors are phosphorylated in the body, chiefly in the liver, by pyridoxal kinase to become the active coenzymes, pyridoxal phosphate and pyridoxamine phosphate.

In the early 1950s, its absence in an infant formula caused an epidemic of convulsions that were curable by pyridoxine injection. In 1968, the National Academy of Sciences recognised its essential nature in human nutrition by assigning it a required daily allowance (RDA).

Biochemical Functions

More than 100 pyridoxal phosphate-dependent enzymes are known to man. The most important functions of this vitamin concern amino acid metabolism. For these functions, pyridoxine provides essential coenzyme reactions that include:

• Transamination — the reversible transfer of an α-amino group between an amino acid and an α-keto acid
• Oxidative deamination of an amino acid to an aldehyde
• Interconversion of the L and D isomers of an amino acid
• Decarboxylation
• Interconversion of glycine and serine
• Conversion of homocysteine and cystathionine to cysteine — failure of the methionine-to-cysteine pathway leads to homocystinuria; the failure of cystathione conversion leads to cystathioninuria
• Conversion of tryptophan to niacin — in the absence of an adequate exogenous source of niacin, pyridoxine deficiency enhances a niacin deficiency

Neurotransmitter Synthesis

Practically all of the compounds identified as neurotransmitters in the brain are synthesised and/or metabolised with the aid of pyridoxal phosphate. These include:

• Dopamine, norepinephrine, serotonin — the principal monoamine neurotransmitters involved in pain modulation, mood, and arousal
• Tyramine, tryptamine, taurine, histamine, γ-aminobutyric acid (GABA), and indirectly acetylcholine
• Serotonin is derived, with the help of pyridoxal phosphate, from 5-hydroxytryptophan
• Glutamic acid decarboxylase with pyridoxal phosphate catalyses the formation of GABA, the principal inhibitory neurotransmitter derived from glutamic acid
• Because pyridoxal phosphate strongly influences pain perception through both norepinephrine and serotonin synthesis, vitamin B₆ insufficiency directly lowers the threshold for pain amplification

Energy Metabolism

Although vitamin B₆ has no primary effect on metabolism, its deficiency indirectly influences both anaerobic and aerobic metabolism:

• Pyridoxal phosphate plays an important conformational or structural role in the enzyme phosphorylase, which is essential to the release of glucose from glycogen — normally the chief substrate for oxidative metabolism in muscle
• Contributes to aerobic metabolism through the degradation of at least 11 amino acids, making the corresponding α-keto acid analogue available to enter the energy-releasing tricarboxylic acid cycle
• Deficiency of pyridoxal phosphate interferes seriously with the disposal of used amino acids, and their reconfiguration for synthesis to new amino acids

Haemoglobin Synthesis

Pyridoxal phosphate plays an essential role as a cofactor in the synthesis of porphyrin, which is a part of the haemoglobin molecule. Adults with proven pyridoxine deficiency may show a microcytic hypochromic anaemia that fails to respond to iron, but the anaemia improves dramatically following treatment with small doses of pyridoxine.

Other Coenzyme Functions

• Reduced absorption and storage of cobalamin (vitamin B₁₂)
• Increased excretion of vitamin C
• Blocked synthesis of nicotinic acid (niacin)
• B₆ acts synergistically with vitamin E to control the metabolism of unsaturated fats, and with vitamin C in tyrosine metabolism
• Essential to lipid metabolism: its deficiency results in reduced absorption and storage of cobalamin and blocked synthesis of nicotinic acid

Insufficiency and Deficiency

The specific enzymatic functions of vitamin B₆ that must be lacking to cause increased neuromuscular irritability and perpetuation of TrPs has not been established. Clear-cut symptoms of pyridoxine deficiency are unusual. Pyridoxine deficiency rarely occurs alone, but is usually seen with deficiency of the other vitamins of the B-complex. Milder, equivocal symptoms appear with inadequate amounts of the vitamin.

Clinical Presentations

Mild insufficiency / chronic partial deficiency: Patients on poor diets were initially observed to have ill-defined central nervous system syndromes of:

• Weakness, irritability, nervousness
• Insomnia
• Difficulty in walking
• Loss of "sense of responsibility"
• Abnormal electroencephalograms

These changes do not respond to treatment with other members of the vitamin B-complex, but are relieved within 24 hours by ingesting pyridoxine.

Established deficiency:

• Dermatological lesions of pellagra (niacin deficiency) may result secondarily from vitamin B₆ deficiency, producing mixed symptoms of pyridoxine and niacin deficiencies
• A disproportionately high percentage of psychiatric patients are folic acid deficient; depression is their most probable psychiatric diagnosis
• In a group of 154 patients admitted to a psychiatric unit of a general hospital, the pyridoxine-deficient patients showed a disproportionately high incidence of depression compared to psychiatric patients without such a deficiency

Diabetic patients complaining of leg cramps, swelling of the hands, and impaired tactile sensation were relieved of their symptoms while taking 50 mg/day of pyridoxine orally.

Carpal tunnel syndrome (CTS): The role of insufficient pyridoxine as a significant factor in CTS is controversial. One study found that pyridoxine supplementation for 12 weeks was effective in the treatment of CTS compared to placebo. A subsequent study failed to support their findings. In some cases, pyridoxine insufficiency may increase the vulnerability of peripheral nerves to entrapment enough to cause the symptoms of CTS.

Pyridoxine Dependence

The need for very large amounts of pyridoxine occurs when one of the specific enzyme systems that require this vitamin is congenitally incomplete. Megadoses (10 times the RDA, or more) of pyridoxine at least partially compensate for the metabolic abnormality. Metabolic dependence on the vitamin is established clinically when both the symptoms and the characteristic abnormal metabolic intermediates recur promptly after resumption of an unsupplemented normal diet.

One should expect considerable variability among patients in their need for pyridoxine. Patients with chronic MPS are a select group who show a high prevalence of vitamin inadequacies. Many of these patients do well on large vitamin supplements — one likely explanation for this apparent partial dependence is the partial expression of one or more of the genetic enzyme deficiencies.

Laboratory Tests

• LC-MS/MS for pyridoxal 5-phosphate (PLP) levels — the preferred current method; reliably reflects vitamin B₆ status in humans. Reference value (fasting): 5–50 mcg/l.
• Plasma pyridoxal phosphate (PLP) concentration — determined by a radioactive tyrosine and apodecarboxylase assay; reliably reflects vitamin B₆ levels in humans
• Measurement of circulating serum vitamin B₆ — a decrease in this blood level is the earliest warning signal of an acute clinical deficiency; in mild-to-moderate chronic deficiency, the symptoms may depend as much on concomitant secondary deficiencies as on the blood level of pyridoxal phosphate
• Valid biological assay for vitamin B₆ requires time and/or special care. Saccharomyces carlsbergensis is the test organism commonly used because it is responsive to pyridoxal, pyridoxal, and pyridoxamine. Unlike most other test microorganisms, it is unable to use D-alanine to satisfy its vitamin B₆ requirement — it is therefore suitable for tests on human blood

Requirements and Sources

Vitamin B₆ is highly conserved in the body. Excretion of vitamin B₆ and its metabolites is rapidly adjusted to changes in the intake of the vitamin. The vitamin B₆ requirement rises roughly in proportion to the increase in protein intake, and with age.

Recommended daily allowances (RDA) by age group:

• Infants 0–12 months: 0.1–0.3 mg/day
• Children 1–8 years: 0.5–0.6 mg/day
• Children 9–13 years: 1.0 mg/day
• Ages 14–18 years: 1.2–1.3 mg/day
• Adults ≥19 years: 1.3–1.7 mg/day
• Pregnant women: 1.9 mg/day
• Lactating women: 2.0 mg/day

Body stores normally contain about 0.60 mg (0.55–0.66 mg) of pyridoxal phosphate/0.45 kg (1 lb) of body weight — a total of about 108 mg in an 82-kg individual; 90% resides in a slow-turnover compartment with a half-life of nearly 33 days; 10% in a fast-turnover compartment with a half-life of about 16 hours.

Best Dietary Sources

Vitamin B₆ is widely distributed in nature, but not in large amounts:

• Liver, kidney
• White meat of chicken, halibut, tuna
• English walnuts, soybean flour, navy beans, bananas, avocados
• Yeast, lean beef, egg yolk, whole wheat, and milk

Fresh milk contains 0.6 mg of vitamin B₆/L (0.14 mg/8 oz serving) — very little — and much is lost when milk is exposed to sunlight for more than a few minutes. Animal sources are less susceptible to loss of the vitamin because of cooking or preserving than are plant sources.

The usual synthetic form of vitamin B₆ is pyridoxine hydrochloride, which is stable in acid solution, but rapidly destroyed by sunlight when in neutral or alkaline solution. This synthetic form is heat stable through most food processing.

Factors That Impair B₆ Availability

• Oral contraceptives — the majority of oral contraceptive users had abnormal tryptophan metabolism characteristic of pyridoxine deficiency; the oestrogenic component is responsible. There is no known contraindication to regularly supplementing the diet of oral contraceptive users with 5–10 mg of vitamin B₆ daily, except minimal cost
• Excessive alcohol consumption — pyridoxine deficiency is aggravated in alcoholics by: (1) reduced dietary intake; (2) impaired absorption of the natural dietary forms of B₆; (3) interference with the conversion of vitamin B₆ to the active phosphorylated form by both alcohol and liver disease. Acetaldehyde, an oxidation product of ethanol, interferes with the metabolism of vitamin B₆ by promoting the degradation of pyridoxal phosphate
• Pregnancy and lactation
• Antitubercular drugs (INH/isoniazid and cycloserine are potent pyridoxine antagonists; symptoms of pyridoxine deficiency due to INH can be prevented by 50 mg/day of oral pyridoxine)
• Corticosteroids
• Hyperthyroidism — the need for vitamin B₆ is increased
• Uraemia — pyridoxine deficiency often occurs in both dialysed and undialysed uraemic patients

Therapy

Pyridoxine is available over-the-counter in 10-, 25-, and 50-mg tablets, and in larger amounts by prescription. Parenteral pyridoxine hydrochloride is supplied in vials in a concentration of 100 mg/ml.

• Oral: 50–100 mg/day to prevent neuropathy
• Intravenous: 100 mg/day in patients with seizures
• A single intramuscular injection of 100 mg of pyridoxine effectively raises the serum level of the vitamin
• Oral supplementation of at least 10 mg per day of vitamin B₆ is strongly recommended for those taking an oral contraceptive
• During pregnancy and lactation, the requirement is markedly increased; augmenting the basic RDA by 2.5 mg was not sufficient to raise blood PLP levels in pregnant women to those of non-pregnant women — monitoring is advisable
• B₆ therapy has provided effective prophylaxis against motion sickness in non-pregnant individuals, both adults and children
• A B-50 vitamin supplement contains 50 mg of pyridoxine and is an ample daily dose to protect nearly all individuals from pyridoxine insufficiency — it can be taken indefinitely as a form of health insurance
• Pharmacological doses of vitamin B₆, ranging from 10–100 mg or more daily, are indicated for the pyridoxine-dependent conditions described above and are non-toxic at these levels

Toxicity

Doses of 500 mg per day given chronically (6 months or longer) produce a peripheral sensory neuropathy and ataxia. Doses over 100 mg per day are unnecessary. Doses as low as 200 mg per day have produced a sensory neuropathy, and constitute a warning against the use of such high pharmacological doses of the vitamin. These constitute a warning against using such high doses.

The Biology of Starvation: Vitamin B₆

Vitamin B₆ occupies a central position in the biology of protein catabolism during starvation — a process that accelerates when carbohydrate stores are exhausted. When glycogen is depleted (within approximately 24 hours of fasting), the body begins to derive glucose from amino acids through gluconeogenesis. This process depends critically on transamination reactions, all of which require pyridoxal phosphate.

The cascade proceeds:

1. Muscle protein is mobilised, releasing amino acids into the circulation
2. Transamination (pyridoxal phosphate-dependent) converts amino acids to their corresponding α-keto acids
3. α-keto acids enter the Krebs cycle or are converted to glucose in the liver
4. Without adequate pyridoxal phosphate, this transamination is impaired — the body cannot efficiently extract gluconeogenic precursors from protein

In states of marginal B₆ nutrition combined with starvation or high protein turnover, the consequences extend to neurotransmitter depletion: serotonin and GABA synthesis both require pyridoxal phosphate, so mood disturbance, anxiety, and sleep disruption often accompany the protein-wasting phase of starvation.

The specific relevance to myofascial pain is that patients with chronic pain who restrict food intake (due to fatigue, depression, or secondary gain), or who consume high-protein diets without adequate B₆, place their neurotransmitter synthesis and their muscle energy metabolism simultaneously at risk.

Related Pages

• Perpetuating Factors — Overview
• Vitamin B₁ (Thiamine) and Trigger Points
• Vitamin B₁₂ (Cobalamin) and Trigger Points
• Folic Acid and Trigger Points
• Pyridoxine — Wikipedia
• Pyridoxal phosphate — Wikipedia
• Vitamin B₆ — Wikipedia
• Transaminase — Wikipedia
• Gluconeogenesis — Wikipedia

References

• Travell JG, Simons DG. Myofascial Pain and Dysfunction: The Trigger Point Manual, Volume 1. 2nd ed. Baltimore: Williams & Wilkins; 1999. Chapter 4, Section C.