Muscle Pain and Rhabdomyolysis

Muscle pain is a very common skeletal muscle phenomenon with distinctive characteristics ( Table 1 ). It occurs after unusual and especially eccentric muscular activity, such as descending a mountain. The pain peaks after 2 or 3 days, but rarely lasts more than a week.

Little or no pain is felt when the muscles are completely relaxed. Movement, such as warming up for a sports activity, will gradually reduce the sensation of pain, but it will return after the activity. When there is pain, the muscles may feel as if they are weak and uncoordinated. While this may be the case, muscle function is usually found to be approximately normal (>90%) when measured objectively with performance tests.

A number of explanatory models have been proposed for muscle soreness, including lactate accumulation and spasms, but the most commonly given is that muscle soreness, also known as delayed onset muscle soreness (DOMS), It is due to cell damage and inflammation. Throughout this article only the term "muscle pain" will be used.

In this clinical review, an alternative mechanism for pain associated with muscle soreness is proposed and compared to the mechanisms underlying muscle injury and rhabdomyolysis.

Table 1 . Differences between muscle pain and exercise-induced rhabdomyolysis. Arrows (↑↓) indicate an increase/decrease (graded from 1 to 4) and parentheses show individual variation.

Muscle activity, particularly eccentric and unusual muscle actions (stretching of contracted muscles), can cause damage to myofibrils and sarcomeres.

The damage is visible under the electron microscope immediately after muscle activity, but may become more extensive in subsequent days. In rare cases, it may take several weeks for muscles to regenerate.

Structural damage to the contractile apparatus, cytoskeleton, and cell membrane leads to both reduced muscle function and apparently local inflammation. Human studies of radiolabeled neutrophil granulocytes, the detection of these cells and of monocytes/macrophages in biopsies of stressed muscle tissue have confirmed that an inflammatory response can accompany muscle pain. Leukocytes may be present within capillaries and between muscle cells, while macrophages can sometimes be found.

It should be noted, however, that the presence of leukocytes and muscle pain do not follow the same time course. Leukocytes are first detected in muscle tissue 48 hours after activity, while muscle soreness is already well established after 24 hours and often decreased when levels of inflammatory cells in muscle tissue were higher. , that is, 4 to 7 days after the activity.

Furthermore, it is possible for subjects with severe pain to have very few or no signs of an inflammatory response in the muscles, and for others with strong signs of inflammation to report mild pain. A causal relationship between muscle pain and “classical” cytokines such as interleukin-6 and TNF-α has not been established in human studies.

Some authors propose that muscle pain begins with the formation of bradykinin. This vasodilator polypeptide is a known inflammatory mediator and can activate nociceptors. Bradykinin is released during muscle activity and binds to the bradykinin B2 receptor present on muscle cells. This activity stimulates increased synthesis of nerve growth factor (NGF) mRNA, as well as the resulting protein synthesis, which is believed to occur within muscle and satellite cells (muscle stem cells).

The time required to produce nerve growth factor could potentially explain the late onset of muscle pain. Growth factor can sensitize C fibers and lead to pressure hyperalgesia, which is typical of muscle pain. However, bradykinin and nerve growth factor do not appear to be the only causes of pain.

The increased presence of glial cell line-derived neurotrophic factor (GDNF) induced by prostaglandin E2 following stimulation of COX-2 activity may also contribute to hyperalgesia (Aδ fibers). The nociceptors that mediate muscle pain in response to nerve growth factor and glial cell line-derived neurotrophic factor, therefore, appear to be the standard C and Aδ fibers.

Since both bradykinin and prostaglandin E2 can be produced locally in the muscle and have autocrine and paracrine effects, muscle pain does not appear to depend on inflammatory cells. This supports that muscle pain is not normally due to classic inflammation of the tissue.

Pain is therefore a form of hyperalgesia. That is, the pain response increases: firm pressure applied to the muscle will be perceived as more uncomfortable and painful than usual. Strong evidence that this is due to sensitization of nociceptors (C and Aδ fibers) does not rule out additional mechanisms at higher levels of the nervous system, for example, in the spinal cord, periaqueductal gray (PAG), or thalamus. This central sensitization may be particularly relevant in rare cases where pain lasts more than 4 to 5 days.

Muscle pain can also be considered allodynia , because nociceptors can respond to mechanical stimuli that do not normally cause pain or discomfort, for example, light pressure or stretching of the muscles. An unconfirmed hypothesis states that mechanosensitive nerves, such as Aβ fibers in muscle spindles, stimulate "pain pathways" at the level of the spinal cord and cause allodynia. Allodynia may also be due to activity in nociceptive C and Aδ fibers, as it has been shown that these fibers can be stimulated by non-painful pressure and stretching of the muscles.

It is reasonable to believe that pain may be a sign that the muscles need rest and relaxation, i.e. recovery.

However, if so, it is not a particularly reliable mechanism since it is possible to have pain even without muscle function being noticeably reduced. On the other hand, pain is usually present, although not always, when the muscles need to rest. Therefore, pain has high sensitivity, but low specificity, as a marker of muscle damage and the need for recovery.

For high-level athletes, this would not be sufficient in any case and they should therefore measure muscle function to determine when additional recovery time is required.

The only sure way to avoid pain is careful and progressive training in exercises that would cause pain if started at a high intensity. Various other measures have been tried in an effort to reduce the pain that is already present. Many of these have no or negligible effect, while others, such as repeated ice baths and massages, can reduce pain to some extent. Much of the calming effect is short-lived and the pain returns quickly, suggesting that the relief may reflect a temporary inhibition of the nervous system.

There are no recognized pharmacological treatments, but it is possible that prophylactic use of non-steroidal anti-inflammatory drugs (NSAIDs), especially COX-2 inhibitors, just before exercise may be effective. On the other hand, both NSAIDs and ice baths can negatively affect muscle recovery and adaptation processes, so that reduction in muscle soreness may come at the expense of reduced exercise benefits. It is unclear whether the mechanism that suppresses muscle soreness is the same mechanism that inhibits exercise adaptation.

The increased incidence of rhabdomyolysis after exercise appears to be due to the increasing popularity of very intense forms of physical activity.

Exercise-induced muscle damage can range from minimal subcellular damage, as occurs during regular exercise, to the breakdown of entire muscle fibers, i.e., necrosis and rhabdomyolysis.

In patients with rhabdomyolysis, the first sign is an immediate and significant reduction in muscle function after physical activity, to less than 50% of maximum strength ( table 1 ). Initial damage includes disruption of the regulatory mechanisms of calcium homeostasis, i.e., ion channels and pumps in the sarcoplasmic reticulum. This increases the resting levels of calcium ions in the muscle cell, resulting in increased activity of several proteases, for example those of the calpain system, as well as phospholipases.

Proteases exacerbate intracellular damage by breaking down the “support beams” of the cytoskeleton (including desmin and dystrophin). If the cytoskeleton collapses, the muscle cell membrane will tear. Increased cell membrane permeability results in not only an uncontrolled release of intracellular proteins such as creatine kinase (CK), but also a further increase in calcium levels. Areas or segments of the muscle cell become trapped in a vicious cycle and die; muscle fibers are rarely damaged along their entire length.

The necrotic process initiates a powerful inflammatory response and subsequent regeneration. Signs of necrosis can be seen after about 48 hours, while the inflammatory response peaks after about a week. Assuming an intact basement membrane, activation of satellite cells (stem cells), and good circulation, regeneration will continue for several weeks. The muscle thus continues its recovery and regeneration processes long after the pain has disappeared.

Rhabdomyolysis is diagnosed by measuring the levels of CK and myoglobin in the blood.

These measures are important since a high myoglobin load can cause kidney failure . Treatment with intravenous saline, crystalloids, and bicarbonate should be considered if CK levels are above 5000 IU/l or five times the upper limit of normal. Rapid initiation of treatment has proven to be crucial in severe cases.

Typical signs and symptoms are severe muscle pain and swelling, as well as muscle weakness, stiffness, and reduced range of motion. An important difference between regular muscle pain and rhabdomyolysis is that the latter also causes muscle pain at rest. However, it should be emphasized that even extreme pain does not necessarily mean rhabdomyolysis. Myoglobinuria, on the other hand, is a sure sign of muscle damage, but not an index of the severity of the condition.

Analysis of urine, myoglobin, and CK in the blood will reveal whether hospitalization is indicated for a patient with rhabdomyolysis.

Certain genetic backgrounds appear to predispose people to rhabdomyolysis, but the most important factor is how one exercises. Special care is required when initiating activity regimens that involve substantial eccentric muscle contractions. It is a common misconception that muscles must be damaged to become bigger and stronger.

Muscle pain is a form of hyperalgesia and allodynia.

The mechanisms appear to be independent of damage to muscle fibers and classic tissue inflammation. The main difference between muscle pain and rhabdomyolysis is that pain should be considered a physiological phenomenon located in the extracellular structures, the muscle fascia and the nervous system (sensitization), while rhabdomyolysis is an intracellular pathological condition of muscle cells.

A physician consulted by a patient complaining of muscle pain should, with the aid of history and palpation of the muscle, be able to determine whether the pain reflects conventional pain or the more dangerous diagnosis of rhabdomyolysis.

Analysis of urine, myoglobin, and CK in the blood will reveal whether hospitalization is indicated for a patient with rhabdomyolysis.