Concept:Vitamin C and TrPs

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Vitamin C (ascorbic acid; L-ascorbic acid) is a water-soluble vitamin of major clinical importance to the muscles because it can prevent much postexercise muscle soreness or stiffness, corrects the increase in capillary fragility associated with ascorbic acid deficiency, and interacts strongly with numerous other vitamins important to muscle function. It is the only reducing substance that specifically regulates dopamine beta-monooxygenase activity in chromaffin cells (adrenal gland medullary cells) in the synthesis of norepinephrine — directly influencing the catecholamine arm of pain transmission.

A practical clinical consequence of vitamin C insufficiency specific to myofascial practice is that scorbutic patients are especially liable to develop post-injection haematomas — a complication of TrP injections that should be actively avoided. The rate of healing of pressure sores was nearly doubled by increasing serum ascorbic acid levels within the normal range from low normal to high normal.

Discovery and History

Scurvy was the scourge of armies, explorers, and sailors on extended trips without fresh food — Vasco da Gama lost 100 of 160 sailors from scurvy on one voyage. In 1928, Albert Szent-Györgyi isolated a chemical that protects some fruits against discolouration and infection when bruised. The chemical is now known as ascorbic acid, or vitamin C. For its discovery, he won the Nobel Prize in 1937.

Some birds and a few mammals (man, monkeys, the guinea pig, and the Indian fruit bat) are unable to convert D-glucuronic acid to L-ascorbic acid, which makes them dependent on exogenous sources. Three exceptional guinea pigs out of several thousand were apparently able to synthesise it — a capability occasionally observed in this species by other investigators; a few people may possess a similar capability. Through recorded history, scurvy was the scourge of populations cut off from fresh produce.

Biochemical Functions

Ascorbic acid is involved in a remarkable number of essential body functions:

Collagen Synthesis

The most abundant protein in mammals is collagen — it constitutes nearly one-quarter of the protein in body tissues. The strong reducing action of ascorbic acid is needed for the hydroxylation of the amino acids lysine and proline to form the protoprotein molecule. This function may be assisted by ascorbic acid inhibition of hyaluronidase. At least two other important body components have an amino acid sequence similar to collagen: the C1q sub-component of complement and the basement membrane of cells.

Without vitamin C to provide the collagen needed for a firm vessel wall, the patient experiences marked capillary fragility and easy bruising, with diffuse tissue bleeding following only minor trauma. This is the mechanism underlying:

  • The classic scurvy presentation of spontaneous haemorrhages
  • Post-TrP-injection haematomas in ascorbic acid-deficient patients — clinically important in myofascial practice
  • Impaired wound healing and delayed resolution of tissue injury

Vitamin C is essential for the deposition of calcium phosphate crystals to form bone — linking ascorbic acid status to bone integrity as well as soft tissue quality.

Neurotransmitter Synthesis

Vitamin C is required for the synthesis of two essential neurotransmitters:

  • Norepinephrine — via regulation of dopamine beta-monooxygenase (the specific enzyme that converts dopamine to norepinephrine)
  • Serotonin — via the hydroxylation of tryptophan to 5-hydroxytryptophan (indirect, through ensuring cofactor function)

Vitamin C is the only reducing substance that specifically regulates dopamine beta-monooxygenase activity in chromaffin cells (adrenal gland medullary cells) in the synthesis of norepinephrine. Both norepinephrine and serotonin are important in the modulation of pain transmission in the central nervous system.

Amino Acid Oxidative Degradation

A 70-kg person on an average diet metabolises about 400 g of protein/day, of which 100 g of amino acids undergo oxidative degradation in a complicated manner that provides the many building blocks for re-generation of protein structures. Ascorbic acid is essential to the oxidative degradation of two amino acids: phenylalanine and tyrosine. With no protein ingestion, some 30 g of indigenous protein continues to be oxidatively degraded.

Free Radical Scavenging and Antioxidant Function

Ascorbic acid is one of the most active reducing agents known to occur naturally in living tissue — it provides a ready source of hydrogen atoms, since it is easily oxidised. This protects many vital tissues from oxidation damage:

  • Protects tissue thiol (-SH) groups, needed to convert plasma transferrin to liver ferritin
  • Enhances the absorption of iron in the gastrointestinal tract
  • Contributes to fatty acid metabolism through the synthesis of carnitine
  • Protects tissue from lipid peroxidation damage

Ascorbic acid is readily oxidised to dehydroascorbic acid, which retains 80% of its effectiveness. Further oxidation renders it inactive. Oxidation in solution is accelerated by heat, light, alkalinity, and a metallic iron or copper vessel.

Immune Function and Stress Response

  • Tissue levels in the adrenal gland parallel those of the corticosteroids; both decrease markedly in response to stress — ascorbic acid participates in the synthesis of corticosterone and 17-hydroxycorticosterone, and may be depleted by its release to the circulation in stress states
  • Increased susceptibility to infectious diseases has been observed consistently among people with scurvy
  • Ascorbic acid has protected experimental animals against the formation of bladder tumours by 3-hydroxyanthranilic acid and against the hepatotoxic combination of sodium nitrite and aminopyrene
  • Combined with acetylsalicylic acid, ascorbic acid caused a significant stimulation of interleukin-6 and may stimulate lymphocyte transformation and polymorphonuclear leukocyte motility
  • In the authors' clinical experience, ascorbic acid helps to terminate bouts of diarrhoea due to food allergy, and to decrease toxicity and TrP irritability caused by chronic infection

Muscle-Specific Effects

  • Prevents or markedly reduces the soreness and stiffness experienced the day after unusually strenuous exercise — 1 g or more of ascorbic acid taken shortly before, or at the time of, exercise prevents this phenomenon; supplementation of 3 g per day blunted reported soreness, the greatest effect occurring at the peak of delayed-onset muscle soreness. This postexercise soreness does not seem to be related to TrPs
  • Reverses some of the electrocardiographic findings associated with increasing age
  • Deficiency in guinea pigs caused dystrophic disorganisation of muscle structures, including fragmentation of myofilaments, swelling of mitochondria, and excessive glycogen accumulation
  • Vitamin C may be important in the treatment of low back pain, presumably because it improves the quality of the connective tissue

Insufficiency and Deficiency

Populations at Risk

In the United States, scurvy due to inadequate dietary intake of ascorbic acid is most likely to occur in:

  • Smokers
  • Alcoholics
  • Older people
  • Infants fed primarily on cow's milk (between the ages of 6 and 12 months)
  • Food faddists and psychiatric patients

A series of 35 patients with alcohol-related illness had a 91% prevalence of ascorbic acid deficiency.

The Smoking–Vitamin C Connection

Cigarette smoking is a major cause of ascorbic acid deficiency:

  • A study of 17 human volunteers who smoked more than 20 cigarettes/day showed that they required 140 mg of vitamin C daily to maintain a steady state plasma ascorbic acid level, compared to a daily intake of only 100 mg in non-smokers
  • Another study showed that smokers needed an additional 65 mg/day on average to maintain serum levels equivalent to those of non-smokers
  • The depression of their vitamin C level is only one reason patients should be encouraged to stop smoking

Clinical Presentation of Scurvy

Scurvy develops after 4–7 months of an insufficient diet. Elderly patients in a chronic disease hospital on an institutional diet with little fresh fruit had an average whole blood vitamin C level of only 0.35 mg/dl. Eight ounces of orange juice daily raised the level to 1.52 mg/dl.

Clinical progression of scurvy:

  • Initially: weakness, lassitude, irritability, vague aching pains in joints and muscles; weight loss
  • Progressive: awareness of easy bruising and even haematomas; gums become swollen, red, and bleed easily; teeth become loose and may fall out (gum symptoms develop only in response to contact with irritants such as dental plaque)
  • Frank: perifollicular hyperkeratotic papules on the buttocks, thighs, and legs; later on arms and back; hairs become buried in the papules; petechiae appear buried around the lesions

The first sign of scurvy is perifollicular hyperkeratosis.

Borderline or subclinical cases are difficult to recognise. Initially, scorbutic patients present with non-specific symptoms of weakness, lassitude, irritability, and vague aching pains in the joints and muscles.

Decreased Absorption

  • Decreased absorption of ascorbic acid is seen in diarrhoeal diseases
  • Increased utilisation occurs in thyrotoxicosis
  • There is evidence of decreasing tissue levels of ascorbic acid with increased age
  • Damage to membranous cell structures by lipid peroxidation appears to contribute to the deterioration of cells in the absence of ascorbic acid's reductive protection of the tissue thiol groups

Laboratory Tests

  • Determination of plasma L-ascorbic acid — based on its reducing properties; available through most medical laboratories
  • A simple, lingual screening test for ascorbic acid deficiency has been developed (Lingual Ascorbic Acid Test, Mineralab Inc.)

Blood Level Interpretation

Status Plasma ascorbic acid
Well nourished > 1.0 mg/dl
Adequately nourished 0.6–1.0 mg/dl
Poorly nourished 0.3–0.6 mg/dl
Deficient < 0.3 mg/dl

Note: ordinary farm animals (horses, pigs) that synthesise ascorbic acid show average plasma concentrations of 0.33–0.40 mg/dl — suggesting that the "well nourished" value of > 1.0 mg/dl in humans, who cannot synthesise the vitamin, may represent a more demanding requirement than these population-derived norms imply.

Requirements and Sources

Body Pool and Metabolism

The body pool of ascorbic acid averages about 1500 mg, and the daily rate of metabolism approximates 3% of the existing body pool. At this rate, it would require 45 mg/day to replenish the pool. Without any replacement, a filled body pool is depleted to the scorbutic level in about 2 months.

Vitamin C is readily absorbed from the upper small intestine, and excess is quickly excreted by the kidney — very little via other portals, and there is no extensive storage. The maximum body pool ranges between 1.5 and 5 g, but may be as low as 1 g.

Absorption efficiency drops significantly at higher intake levels:

  • 70% of 180 mg is absorbed
  • 50% of 1.5 g is absorbed
  • 16% of 12 g is absorbed

Unabsorbed vitamin C may cause diarrhoea due to an osmotic effect.

The half-life in man ranges from 13–30 days; the larger the intake, the shorter the half-life.

The basic recommended daily allowance is 200 mg/day (updated recommendation). At single doses of 500 mg and higher, the percentage of vitamin C absorbed declines — absorption is complete at a dose of 200 mg, but less than 50% of a 1250 mg dose is absorbed. Plateau plasma vitamin C is nearly maximal with the ingestion of 200 mg/day with no adverse effects, and is maximal at 400 mg/day.

Best Dietary Sources

Excellent sources (containing more than 100 mg/100 g raw food):

  • Broccoli, Brussels sprouts, collards, kale, turnip greens
  • Guava
  • Sweet peppers (all colours)

Less rich but valuable sources:

  • Cabbage, potatoes (commonly eaten in large quantities)
  • Citrus fruits — the fresh juice of a large orange contains about 50 mg; thus 4 oranges would supply the 200 mg daily need

However, loss of the vitamin in processing or storage may be large:

  • Canned tomatoes retain a high percentage of their ascorbic acid content (20 mg/100g) because of the acid environment
  • Cooking water contains substantial amounts — do not discard the pot liquor
  • Vitamin C is highly soluble in water and is often discarded in the pot liquor of cooked foods
  • Further oxidation renders it inactive; oxidation in solution is accelerated by heat, light, alkalinity, and a metallic iron or copper vessel

Therapy

Prescription

Prescription of ascorbic acid can be based on the new recommended dietary allowance of 200 mg/day. At single doses of 500 mg and higher, the percent of vitamin C absorbed declines. A physiologic dose of 400 mg daily ensures a normal metabolic pool of ascorbic acid to meet emergency demands.

  • The optimal intake required depends on highly variable stress factors — in sickness there is greater tolerance for vitamin C than in good health; this suggests that megadoses may be therapeutic when in poor health
  • The vitamin C requirement in women taking oestrogen, or an oral contraceptive agent, may increase 3- to 10-fold, requiring daily amounts of up to 500 mg
  • We consider it wise to supplement the diet routinely with 500 mg of a timed-release preparation daily — this supplementation programme is another cost-effective form of health insurance; vitamin C supplementation becomes increasingly critical with advancing age

Toxicity

  • Vitamin C daily doses above 400 mg have no evident value
  • Oxalate and urate excretion were elevated at 1000 mg/day of vitamin C, increasing the risk of renal stone formation
  • Safe doses are therefore less than 1000 mg/day
  • Scorbutic symptoms may develop in persons suddenly withdrawn from megadose therapy, just as these symptoms may appear post-partum in babies born to megadose-treated mothers
  • A daily megadose can cause watery diarrhoea that has been misdiagnosed as spastic colon, and can cause a non-specific urethritis that has unnecessarily led to extensive studies for venereal infection

Important Drug Interactions

  • Increased absorption of some metallic ions produced by supplemental vitamin C is desirable (iron), but undesirable in the case of mercury
  • Ascorbic acid supplementation increases the amount of warfarin required to maintain the same therapeutic effect on blood clotting
  • Supplemental vitamin C lowers the prothrombin time in patients on warfarin
  • Antacids destroy the effectiveness of ascorbic acid and should be taken separately so they are not mixed in the stomach
  • Ascorbic acid combined with acetylsalicylic acid caused a significant stimulation of interleukin-6

The Biology of Starvation: Vitamin C

Among the vitamins, ascorbic acid occupies a unique position in the biology of starvation because humans cannot synthesise it — unlike most mammals — and because it governs the structural integrity of connective tissue, the immediate response to physiological stress, and the synthesis of the catecholamines that mediate the stress response itself.

The starvation cascade for vitamin C unfolds as follows:

Collagen collapse — the structural consequence: Without continuous ascorbic acid, the hydroxylation of proline and lysine in collagen precursors ceases. Old collagen turns over and is not replaced; the supporting matrix of blood vessels, skin, tendons, and bone dissolves progressively. The clinical sequence — perifollicular haemorrhage → ecchymoses → haemarthrosis → subperiosteal haematoma → spontaneous bone fracture — traces the loss of structural integrity from the finest vessels outward.

This has direct relevance to myofascial injections: ascorbic acid-deficient patients form haematomas after needling at doses of local anaesthetic that would cause only minor bruising in a replete patient. The clinician must check vitamin C status before initiating injection therapy.

Adrenal exhaustion and the stress cascade: The adrenal gland is the tissue most richly supplied with ascorbic acid. Both the adrenal cortex (for cortisol synthesis) and the adrenal medulla (for norepinephrine synthesis via dopamine beta-monooxygenase) depend critically on ascorbic acid. In starvation combined with stress — illness, injury, infection, or the psychological stress of chronic pain — adrenal ascorbic acid is rapidly consumed. The inability to mount an adequate adrenocortical and catecholamine response in ascorbic acid depletion creates a vulnerability to physiological insult at the very time that resistance is most needed.

The immune collapse: Ascorbic acid is required for neutrophil function, lymphocyte proliferation, and antibody synthesis. In starvation-associated vitamin C depletion, wound infection becomes lethal — historically accounting for a large proportion of scurvy deaths, which were often attributed to the infection rather than the underlying nutritional deficiency.

Pain amplification: The depletion of norepinephrine and serotonin synthesis capacity (both dependent on ascorbic acid) in prolonged insufficiency creates a state of impaired descending pain inhibition. This directly increases TrP irritability and pain amplification, and produces a clinical picture indistinguishable from central sensitisation.

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.
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