Martin McDonagh
School of Sport and Exercise Sciences, University of Birmingham, Birmingham, UK

https://doi.org/10.36866/pn.84.22

Aaaagh! Just back from a marathon on your 25th birthday? Just gone to bed on your 65th? Cramp! Cramp is a condition of two surprising extremes: the old lying very still and the young at full pace. So what is cramp? How can it be prevented? What do we know about its physiology? I’ll try to answer all three questions, but first, a definition: cramp is a painful involuntary muscle contraction that occurs in part of a muscle, feels like a hard knot and has an active electromyogram. Cramps can spread from the original focus or start again from a new one.

Circumstances

Most muscle cramps are benign but are also a sign in pathological conditions such as lower motor neurone disorders (e.g. amyotrophic lateral sclerosis: ALS), metabolic disorders (e.g. uraemia) and acute extracellular volume depletion (e.g. in cholera). For further information on these see Miller & Layzer (2005). Writer’s cramp and other cramps associated with dystonia are believed to have an origin in the basal ganglia and are not covered here. Cramp occurs in patients undergoing haemodialysis, in response to some drugs, e.g. diuretics and in 30% of pregnant women in the last trimester. It mainly strikes when muscles are fully shortened and it is probably impossible to evoke cramp in a lengthened muscle (Bertolasi et al. 1993). Women appear to be more susceptible than men (Jansen et al. 1991). Muscles of the calf (84% of cramps ) and feet (39%) are the most susceptible followed by the hamstrings and the quadriceps (Jansen et al. 1991). Any muscle can be affected as illustrated by Moss (1923) writing about the miners of the Agecroft and Pendleton pits: “If a man is attacked whilst lifting a full tub onto the rails cramp might occur in the arms, legs, or abdomen. If the latter, the man is put out of action immediately, the contortion of the abdominal muscles being so great as to form a lump the size of a cricket ball”.

Cramp follows muscle fatigue and endurance athletes often experience cramp towards the end of their competition. At work, cramp often struck at the end of a shift in profusely sweating men doing hard physical jobs in hot environments. Labourers building the Hoover Dam on the Colorado river in the 1930s were particularly prone to attacks. In 1900 the French ship Bugeaud in the Red Sea reported forty-two cases for its stokehold but by1928 a correspondent to the Lancet noted that the change from coal to oil as fuel had dramatically decreased the incidence of engine room cramp. During the early 20th century research into these heat cramps (e.g. Moss, 1923) did not get much further than suggesting that muscle fatigue, low plasma sodium and low plasma volume were the most likely causes.

In contrast to the race track and the stokers’ hold, cramps also occur in bed and these rest cramps are more frequent as we get older and can seriously erode quality of life (Jansen et al. 1991). In a study of 233 people aged 60 years or more, 40% had cramps more than three times a week, and 6% reported daily cramps. The prevalence of nocturnal cramp in old age may be related to reduced limb blood flow as another study showed an association with peripheral vascular disease. Sleeping with the foot plantar flexed will also increase the incidence of calf cramp. The kick in swimming also leads to a very shortened and unloaded calf muscle which may be part of the explanation for swimming cramps. Anecdotally swimming cramps are also more common in cold water.

Cures

Like death and taxes, cramp has always been with us and so have bizarre preventative measures and cures. At the Science Museum in London you can see a medieval cramp ring. These were blessed and distributed by the monarch on Good Friday at the Chapel Royal in the Tower of London and were worn to cure ‘the crampe’ and ‘the falling sickness’ (epilepsy) (Fig. 2). Legend tells that a pilgrim returning from Jerusalem presented the original ring to Edward the Confessor and explained its miraculous properties to the king. Much later in 1809 Parr’s London Medical Dictionary prescribed “tar water every night and morning” or “holding a roll of brimstone”. Rather more scientifically, H. Charlton Bastian in Richard Quain’s Dictionary of Medicine (1894) recommended contracting the antagonist or firm pressure around the thigh or on the sciatic nerve. However, as late as 1972, yes 1972, a letter to the Lancet proclaimed the efficacy of a flat horseshoe magnet 3 inches in length placed between the mattress and the lower sheet. Pickle juice has also featured in recent home remedies. In the past, preventative measures for cramp in the heat were rather more rational and involved the worker taking isotonic drinks or more salt in food, but this in itself may have bad effects not least on blood pressure.

Drugs have, of course, been tried. Wolf first described the positive effects of the anti-malarial drug quinine on myotonia. Early work on isolated preparations found a curare-like inhibitory effect on the postsynaptic neuromuscular junction and a potentiating effect on the twitch action potential of curarised muscle. Quinine also presynaptically reduces the quantal content of the end-plate potential. Quinine is still the most effective drug; however, the US FDA banned over-the-counter sales in 1994 because of drug interactions and side effects such as tinnitus and more rarely low platelet count. In 2010, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update stating that its use should only be considered when cramps cause regular disruption of sleep and non-pharmacological measures have not worked. Incidentally, Indian tonic water still contains quinine concentrations close to the effective range but patients with compromised neuromuscular transmission should avoid this drink. Other drugs have been tried which aim to partially block transmission at different sites from spinal cord to muscle membrane (Miller & Layzer, 2005). Although success has been claimed (e.g. for the calcium channel blocker verapamil) none are used routinely.

So much for preventative measures; what can be done to relieve an attack? In electrolyte disturbances, saline given orally or, in the case of dialysis, intravenously usually ends the cramp. However, the most immediately effective acute measure is to lengthen the muscle by external force or by contracting the antagonist which will also evoke reciprocal inhibition. It is not yet certain whether regular muscle stretching or stretching before sleeping prevents cramp.

Causes

Cramp is associated with ischaemic-like pain but not paraesthesia. Recent research suggests that ischaemic pain arises when ATP, and lactate, which are released from oxygen-deprived, contracting muscle, increase the ability of acid-sensing channel number 3 (ASIC3) on nociceptors to respond to a subtle decrease in pH. It is very likely that a similar mechanism gives rise to the pain of cramp.

The main feature of cramp is the muscle contraction. Here the major debate is whether it has a central or peripheral origin i.e. spinal or supra spinal vs. nerve endings or muscle fibres. There are several findings which support the central hypothesis. Cramp can be evoked in very susceptible individuals by stimulation of IA afferents using an H reflex technique (Baldissera et al. 1994). It is suppressed by contraction of the antagonists (Norris et al. 1957) and by cutaneous (Baldissera et al. 1994) or tendon stimulation. Norris et al. (1957) reported synchronous firing of different motor units and Ross & Thomas (1995), using tungsten electrodes, recorded potentials indistinguishable from those found in voluntary contractions. All these findings suggest coordination from the spinal cord.

The peripheral hypothesis also has experimental findings in its favour. Cramps spread outwards from a focus into neighbouring muscle tissue whereas voluntary contractions activate motor units throughout the muscle (Roeleveld et al. 2000). Some of the best evidence comes from work on twitch-like muscle fasciculations. Cramp is often associated with spontaneous benign fasciculations and the mechanisms are probably identical. Denny Brown & Foley (1948) found that single fasciculation potentials changed shape suggesting locally activated fractions of motor units. Another result showing the peripheral origin of some fasciculation potentials was their observation that potentials moving antidromically from the periphery occasionally cancelled voluntary potentials descending from the spinal cord. Later, authors using experimentally induced collisions, showed that most fasciculation potentials have a peripheral origin. Finally, Bertolasi et al. (1993) reported a critical result favouring the peripheral hypothesis. They found they could still evoke cramps by electrical stimulation distal to a complete peripheral nerve conduction block. They also noted that even in muscle with a complete nerve block, lengthening still suppressed the cramp, suggesting a peripheral mechanism for this effect as well.

If the initiation of cramp is peripheral where and when does it occur?

A working hypothesis is that spontaneous activity (ectopic firing) arises in peripheral nerve endings which then spreads to neighbouring excitable tissue by direct contact (ephaptic spread), a process which probably also has a role in epileptic seizures. There is some evidence which allows us to narrow down to a possible site. For example, the ectopic foci for fasciculations are probably at or beyond the motor nerve endings as peripheral nerve block does not abolish them (Minetto et al. 2010). Curare and botulinum toxin both block cramp so the foci must be proximal to the muscle membrane and prior to the endplate. The most likely region is the last unmyelinated part of the nerve endings where sodium and potassium channels are located.

Ectoptic and ephaptic activity is most likely to occur when: axons are closely apposed; there is high extracellular resistance; electrolyte balance is disturbed; and there is prior repetitive discharge. All of these conditions are also associated with cramp. A shortening and contracting muscle will press axons and muscle fibres closer together. It has been calculated that pressures in a fully contracted human gastrocnemius can rise to 43.79 kPa (328 mmHg), which is more than sufficient to also cause ischaemia. Osmotically induced cell swelling will also crush muscle fibres and nerve endings together and increase the likelihood of ectopic firing. For example, hyposmolar solutions increase, and hyperosmolar decrease, ectopic type firing in hippocampal slices. Stewart et al. (1972) suggested that such cell swelling occurred in dialysis and could be responsible for dialysis cramps. Volume expansion with either saline or hypertonic dextrose relieves these cramps. The equal effectiveness of dextrose highlights the role of low plasma volume as a cause of cramp.

There is considerable evidence that extracellular ionic disturbances are related to ectopic firing in nerve and fasciculations in muscle. The exact contribution of potassium and sodium concentrations and currents has not been definitely determined but these must be prime candidates. There are some clues, however. The fasciculations of ALS appear to be due to both persistent sodium currents, and reduced potassium currents. Potassium accumulates extracellularly around fatiguing muscle and prolonged stimulation of axons also results in extracellular K+ accumulation. It is also possible that acetylcholine acting presynaptically may generate ectopic activity in motor nerve endings.

Cramp is more common in shortened muscle. A possible explanation is that the local concentrations of these ions and molecules may be increased by reduction of extracellular space in extreme shortening, thus making ectopic and ephaptic activation more likely. Finally, ephaptic spread is also more likely if cells fire repetitively and in this context it is interesting to note that the higher the frequency the shorter the duration of the tetanic stimulation required to evoke cramp (Bertolasi et al. 1993).

From the discussion so far it would appear that the hypothesis for a purely ‘peripheral’ origin of cramp has the most direct and circumstantial evidence in its favour. However, recent careful work by Minetto et al. (2010) has challenged this view. They showed that electrically evoked cramps do occur with a proximal nerve block but only lasted less than 3 s. Only in the unblocked condition did full-blown cramps lasting 30 s or more occur. A sensible interpretation of these results is a synthesis of the peripheral and central hypotheses in which the initiation of cramp is local but its development needs spinal connectivity.

In summary, it is surprising that we still know so little about cramp, a common phenomenon which will certainly dash the dreams of many a 2012 Olympic hopeful. Any future breakthrough in understanding and treatment will require research on both the mechanisms of ectopic foci, and on the role of spinal circuits in both animal and human models of cramp.

In the meantime keep your muscles stretched, your drinks long and your salts balanced!

References

Baldissera F, Cavallari P & Dworzak F (1994). Motor neuron ‘bistability’. A pathogenetic mechanism for cramps and myokymia. Brain 117, 929–939.

Bertolasi L, De Grandis D, Bongiovanni LG, Zanette GP & Gasperini M (1993). The influence of muscular lengthening on cramps. Ann Neurol 33, 176–180.

Denny-Brown D & Foley JM (1948). Myokymia and the benign fasciculations of muscle cramps. Trans Assoc Am Phys 61, 88–96.

Jansen PH, Jooster EM, Van Dijck J, Verbeek AL & Durian FW (1991). The incidence of muscle cramp. J Neurol Neurosurg Psychiatry 54, 1124–1125.

Miller TM & Layzer RB ( 2005). Muscle cramps. Muscle Nerve 32 431–442.

Minetto MA, Holobar A, Botter A, Ravenni R & Farina D (2010). Motor unit discharge properties during muscle cramps electrically-elicited after peripheral nerve block [abstract]. Motoneuron Meeting 2010: Towards Translational Research in Motoneurons, Paris, France, July 9–13.

Moss NK (1923). Some effects of high air temperatures and muscular exertion upon colliers. Proc Roy Soc B 95, 181–200.

Norris FH , Gasteiger El & Chatfield PO (1957). An electromyographic study of induced and spontaneous muscle cramps. Electroencephalogr Clin Neurophysiol 9,139–147.

Roeleveld K, van Engelen BG & Stegeman DF (2000). Possible mechanisms of muscle cramp from temporal and spatial surface EMG characteristics. J Appl Physiol 88,1698–1706.

Ross BH & Thomas CK (1995). Human motor unit activity during induced muscle cramp. Brain 11, 983–993.

Stewart WK, Fleming LW & Manuel MA (1972). Muscle cramps during maintenance haemodialysis. Lancet 7759, 1049–1051. (A full reference list is available from the author: m.j.mcdonagh@bham.ac.uk)