Muscle aches and statin intolerance – when is a raised CK actually OK?

A few weekends ago, my kids dragged me to a high ropes course and of course, laughed hysterically at my squeals, trembling legs and acute onset acrophobia. The next morning, let's just say I knew a thing or two about aching muscles…

But when are aching muscles more than just, well, aching muscles? And when might checking a creatine kinase (CK) be important?

First- a quick CK recap. CK is an enzyme used by high energy cells (think heart, muscle and brain) that can be used as biomarker of muscle damage when it is released into the blood. Although it’s sadly not quite that simple, as levels also vary depending on age, sex, ethnicity and any body-building tendencies of the patient in front of us. This means a small CK increase for your granny may indicate a greater degree of muscle damage than a large increase for that MAMIL racing you at the traffic lights. Levels can also be raised without any muscle symptoms and unhelpfully, there is no clear correlation between CK levels and the extent of a muscle injury.   

Confused? Don’t panic. Luckily, a useful article in the BMJ’s fantastic rational testing series, ‘Investigating raised Creatine Kinase,’ is on hand to help us make sense of all this. 

First up, what can cause a raised level? 

Often, this will either be a normal variant, or due to the acute effects of exercise. Any cause of muscle trauma (including seizures, surgery, crush injuries or long lies) can also increase levels, as can many drugs (commonly macrolides, antifungals and statins.) Frequently a rise will be multifactorial - think about the keen sportsperson who normally takes a statin without problem, but pushes themselves on a hot day without adequate hydration and thus ‘runs’ into trouble with a raised CK.

So when should we check a CK? 

In any patient with symptoms suggesting muscle damage, inflammation or injury from any of the causes above, or when it comes to statins, as per NICE guidance:

1. If we are considering starting a statin in people who have had “persistent generalised unexplained muscle pain”. 
2. If a patient on statin therapy develops muscle pain. 

How do we interpret results? 

A helpful flowchart is provided in the BMJ article, but this essentially depends on the level. 

If the level is >10x the upper limit of normal (ULN), we must think rhabdomyolysis. The patient will probably present with pain, swelling or weakness and may report dark urine due to myoglobinuria. These patients warrant urgent referral for assessment of renal impairment as patients may require urgent dialysis.

If the level is 4-10x ULN, we need to consider secondary causes, so repeat the CK and check bloods. If the CK is due to exercise or trauma this will generally resolve with rest and hydration, causative medications should be stopped and any underlying metabolic or autoimmune conditions will need treatment. 

If the rise is small, i.e. <4x ULN, the majority will be incidental and resolve spontaneously. A CK secondary to high-intensity exercise will typically normalise within 3-7 days, so recheck after 1-2 weeks to ensure this is the case. There will also be patients with recurrent, stable, high creatine kinase (‘normal for them’) and presuming they are asymptomatic, they need no further investigation.

What about statins? 

No article about CK would be complete without touching on statins.  Even though statins only actually result in a small 3% increased relative risk of muscle pain or weakness compared to placebo (see Rob’s blog, or last year's Lancet meta-analysis if you don’t believe me), muscle pains are still common, and statins have a powerful nocebo effect. Furthermore, recent NICE guidance means we may be prescribing statins to a whole heap more patients. It's therefore important we have a clear plan of what to do when it comes to any aberrant CK’s. 

If a patient develops new symptoms on a statin - including pain, tenderness, or weakness - we should check a CK. Presuming it’s <4x ULN, most can be managed by a watch-and-wait approach, reducing the dose, or switching statin. If the CK is higher, or the symptoms significant, the statin should be stopped and the CK rechecked at 4-6 weeks. If normalised, a rechallenge with a lower dose or different statin is sensible, otherwise, refer for specialist advice. The NHS statin intolerance pathway provides a helpful flowchart to guide you and avoid the risk of labelling a patient as ‘statin intolerant’ too quickly. Options for the minority who are genuinely statin intolerant are discussed in the NHS Lipid Management Summary Guidance.

Counterintuitively, low-intensity statins are no less myotoxic than high-intensity statins, and there's no good evidence to support the improved tolerability of any one statin over another. Pragmatically, therefore, try cost-effective generic statins first and remember a low-dose statin is still better than nothing. For patients who do not tolerate daily statins, alternate day or twice-weekly dosing may work, and rosuvastatin and atorvastatin are good options due to their longer half-lives.

So next time you’re faced with that errant CK in your inbox, or a patient who tells you they stopped that ‘nasty statin’ because it made them achey, don’t despair. Work your way through the flow chart, or our helpful KISS, don’t give up on those statins too quickly, and don’t panic. Dealing with that CK really is going to be OK.