69. PAIN LEVELS

If one thing defines a severe floxing that is pain. Too many times it is a matter of all sorts of pains at all times and unremitting. The three main group of flox pains are:

Neurological, due to the nerve toxicity, experienced statically and with every movement

Muscular, associated with all the muscles of the body

Joint pains, mainly tendinosis, bursitis, enthesitis, synovial problems

Pain plus insomnia makes life absolutely miserable. Pains of great intensity that interfer continously with the daily life and the patient's mood can be present for five and more years.

Unfortunately, there is no pain reliever that works for all floxed persons, and all the experiences to treat the neurological pain, muscular pain and joint pain of floxed persons have contradictory outcomes.

Pain levels experienced throughout the floxing can range from very low to the maximum on a 10-point scale. Pains of the maximum severity: stabbing, jabbing, tearing, and ripping, can be felt when a joint or limb collapses neurologically or just because of no apparent reason. These pains are described as higher than passing a kidney stone or rupturing a testicle, for instance, and can completely block the affected joint. By blocking a joint we mean that the patient intentionally avoids the least movement that affects it, because of the inmense pain. For instance, when moving or bearing weight on a foot is so maddening painful, that the floxed person avoids at all costs any movement, any maneouver and any weight bearing on that foot for a week or two, until de pain becomes more endurable.

Intermediate pains are common with mono-neuritis in legs, arms and neck, especially at night and with some minor movements. Low intensity pains (that correspond to myalgias) typically spread all over and correspond to the "normal" state of a floxed person: just feeling like a person that is 40 years older than his current age. See later for more information on neurological pains, how they can affect daily life and how little can be done to palliate them.

70.CONSTANT PAIN ALL OVER. MYALGIAS

Besides the neurological pains, in severe reactions, constant, intense and body-wide pains are very common. Basically they are drug-induced myopathies, again probably secondary to the vasculitic reaction. The major symptoms in drug-induced myopathies are proximal muscle weakness (quads, hamstrings, shoulder, biceps, triceps), slightly increased muscle enzyme levels (for instance CPK, although sometimes can be normal), electromyographic changes and histological injuries. Quinolones induce painful myopathies associated with neuropathies that could be called painful neuro-myopathies. According to the established medical research, typical of these neuro-myopaties is a free period between the beginning of the treatment and the appearance of symptoms, and incomplete resolution after withdrawal of the treatment.

In fact, myopathy is defined as any abonormal condition or disease of the muscle tissues, commonly involving skeletal tissue. Many drugs have been implicated as causes of myopathy, although quinolones are frequently left out by medical manuals, normally because each manual copies from other previous fact sheets and there is little new research behind new editions. The widespread myopathies caused by the quinolones are another "postmarketing anecdotical finding" according to laboratories, and are not still regarded as a common source of muscular pain.

Quinolone myopathy, like other drug-induced myopathies, usually develops insidiously. The onset of clinical manifestations can occur days to months after exposure to the causative agent, according to Zuckner and Mastaglia (see references). Commonly, patients present with non-specific complaints of progressive, generalized muscle weakness, muscle pain (myalgia) or fatigue. Severe reactions to quinolone antibiotics (prolonged courses or high doses) present with severe myalgias and debilitating weakness, especially in proximal muscles (quads, hamstrings, upper arms) that leave many floxed people completely crippled, bedridden or in a wheelchair for months.

Drugs may cause muscle injury by direct, indirect, or immunologically mediate mechanisms. Again, we do not know the exact mechanism of injury behind the quinolones but it might be off all types, including a drug-induced immunological action directed at the muscle, already mentioned as immune complex-mediated myositis. It is a type of inflammatory myositis and that might be the reason why floxings resemble other inflammatory illnesses so much.

Nevertheless, we do not have the means to discover the mechanism of the injuries, and the medical class is not devoting enough research to find an answer. As a consequence only a guess can be attempted. Quinolone myopathies could also have a direct myotoxicity, as the toxicity exhibited by the statins (used to treat high cholesterol, associated with vacuolar myopathy), or other common drugs that cause mitochondrial myopathy, which symptoms also resemble very much a floxing reaction.

The muscular pain caused by quinolones is defined by some doctors that have treated difficult cases of quinolone toxicity as a manifestation of a sort of "low grade" myoglobinuria-rhabdomyolisis. These illnesses, when fully developed, are very dangerous, and have a fatal potential. There are many reports of fulminated deaths caused by quinolones due to both of these mechanisms. But in general, for floxed persons, they tend to show a more manageable profile, although very damaging.

Severe reactions typically show a slight elevation of the serum myoglobin levels that can also stay at the upper normal range for some 4 years or more. For the same length of time the CPK enzyme (creatinephosphokinase) may be elevated--normally on the hundreds, or low thousands figures.

The cause of both alterations probably is muscular necrosis caused by the quinolone induced vasculitis. Symptoms are very well known for long term floxed persons: generalized pain, decreased range of motion, stiffness, soreness; and all of the symptoms increase with activity.

71. WHAT IS HAPPENING IN OUR MUSCLES?

The pathology exhibited by the floxed persons is necrosis of muscle fibers with a releasing of muscle components into circulation. The doctors consulted theorize that muscles are injured due to both:

a rise in free intracellular calcium due to damage to muscle sarcolemma and a failure of energy supply within muscle cell.

an activation of calcium-dependent neutral proteases & phospholipases that destroys myofibrillar, cytoskeletal, and membrane proteins and the ensuing lysosomal digestion of muscle fiber contents.

Typically, the severely affected floxed person exhibits clinical features of muscle involvement (weakness, stronger proximal, rather than distal; discomfort in terms of pain and tenderness; swelling). There are also many case reports of renal injuries like acute interstitial nephritis, renal impairment, proteinuria (i.e foamy urine), and extremely severe rhabdomyolysis that can be fatal, acompanied by a dark urine (that is tea colored). A good deal of floxed persons also have a fever for some months when the crisis is more acute.

As explained before, many sedentary floxed persons believe that they are healed two years earlier on average than when they are actually cured, because the symptoms of small neuromuscular damage do not become evident unless the patient performs some type of physically demanding activity.

The main determining factors for neuromuscular pains in affected floxed persons seem to be: increased age, exercise, fasting, hypokalemia (low potassium levels).

The main tests to be performed in order to assess the renal involvement of the muscular destruction are:

Hyperkalemia (high potassium levels). High levels are caused by muscle breakdown and also by renal failure.

Hypokalemia (low potassium levels): Causes myoglobinuria. Also painless proximal weakness.

Hypercalcemia (high calcium levels): Due to release from muscle and possible reduced renal excretion.

Hypocalcemia (low calcium levels): Due to binding by damaged muscle & hyperphosphatemia (high phosphorus levels)

Hyperphosphatemia & Tissue calcification: Due to release of organic & inorganic phosphates from muscle.

Test also for serum (blood) levels of myoglobin (high levels in muscular destruction and renal compromise, may be caused by quinolonic ischmemic vascular occlusion), hemoglobin, CPK (muscular, heart and brain destruction), lactate (see below), carnitine (if low the quinolones have affected the β-oxidation process)

Test also for urine levels of myoglobin, albumin and hematuria

Special meaning of the test for serum lactate: There is no increase with exercise in glycogenoses (disorders of the glycogen storage); but there is a rise with minimal exercise when the quinolones have induced a mitochondrial disorder.

The ultimate test is a muscle biopsy usually showing destruction of small nerves, plus scattered muscle fiber necrosis and degeneration.

The quinolone family of drugs specifically may cause:

glycogen metabolic disorders, especially those altering the aldolase, lactate dehydrogenase, phosphoglycerate kinase and phosphorylase kinase.

figure 15

fatty acid oxidation disorders

mitochondrial disorders, the most common through a deficiency in coenzyme Q10.

This chart shows (figure 15) the evolution of the CPK levels of a 36 year old floxed person that was perfectly healthy prior to suffer a reaction that has been classified by himself as SEVERE. (Reproduced with permission). His base level of CPK before the floxing was around 100 U/l. The maximum level of CPK considered normal is 170 U/l (blue stright line), and figures above that are considered a sign of excessive muscle destruction. These levels of the diagram are total CPK. The floxed person was tested for the specific CPKs for heart, brain and musculoskeletal muscle, and the first two were within normal levels, althouh high, and the latter was abnormal for nearly four years. The floxed person had 3 measures of CPK prior to the floxing (all normal), and 26 afterwards in a period of 4 years. This chart corresponds to one floxed person, but we have recorded the data of another 5 individuals, and show patterns that are somehow similar.

The evolution shows a first phase of one and a half year where the level is close to the maximum (170 U/l), and then starts to rise up to month 45, with some peaks in the middle probably due to a fatiguing exercise or similar before the test of that day. Only at month 46 values descended below the maximum, although still being borderline.

Pain is a subjective measure, but the floxed person did not feel much pains during the first 6 months (but extremely strong tendinitis) and then the pains increased steadly to peak at month 32, with pains rated as 8/10. The overall aches and pains all over the body descended while approaching the fourth year and at month 48 (4 years out) the pain level is rated as 5/10.

So, perhaps the high CPK levels are a measure of the muscular pains, stiffness and intolerance to exercise. Please, notice that we use the term "intolerance to exercise" to designate a flox syndrome characterized by high pains, stiffness and soreness experienced after vigorous activity. Normally, doctors define intolerance to exercise to the inability to exercise because of extreme fatigue, high or low heart beats, and other abnormal responses of the body to exercise.

The coenzyme Q10 (also called ubiquinone) deficiency deserves a special consideration. Clinically it manifests as exertional fatigue, high myoglobinuria (precipitated by fever, and mild to moderate exercise), proximal weakness (quads, hamstrings, biceps, triceps) and afflictions to the central nervous system (mainly cognitive impairment). On a biopsy, muscles can show ragged red fibers with prominent lipid accumulation. Some floxed persons have been repeteadly tested for coenzyme levels in blood, resulting in extremely low readings. It seems that in those cases supplementation should help. Coenzyme Q10 also intervenes in the metabolism of cholesterol. Other drugs that deplete the body of Q10 are statins (drugs for lowering cholesterol).