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The primary care management of myalgia in patients who are taking statins

Working Party—Kassianos, Armitage, Gill, Morrell, Reckless, Viljoen

This guideline was developed by a multidisciplinary expert panel: Kassianos G et al with the support of a grant from AstraZeneca. Click here for full disclaimer.

Definition of myalgia and associated terms

  • Myalgia: muscle pain, tenderness, or weakness without creatine kinase elevation* that is generalised and symmetrical and present for 3 or more days
  • Myositis: muscle symptoms with increased creatine kinase levels (typically >5 × ULN and <20 × ULN)*
  • Rhabdomyolysis: muscle symptoms with marked creatine kinase levels that are typically >20 times ULN with creatinine elevation and renal failure (usually with brown urine and urinary myoglobin)

* This depends on the baseline level for a particular patient and a normal range based on the general population may not be appropriate for an individual patient. Higher levels are seen in some populations (e.g. those of African or Caribbean origin), in highly muscular individuals or after strenuous exercise, and a decline is common with increasing age

The elevated level of creatine kinase should return to normal within a few days of statin withdrawal

  • It is clear that statins can rarely cause myositis and even more rarely, rhabdomyolysis. It is much less clear that statins are responsible for myalgia with normal (or even mildly raised) CK levels
  • It is important to remember that muscle pain presenting in the majority of patients taking statins is unlikely to be due to the statin, and in the case of myalgia, where significant CK elevation has been excluded, careful consideration of the options should precede statin withdrawal

Assessing myalgia in primary care

Patient history and examination

  • Obtain a detailed patient history—describe the symptoms; when it is present, statin-associated muscle pain tends to:
    • Be proximal
    • Worsen on exercise
    • Develop after 1 week of statin treatment but may also develop if there are changes to other treatments over time (e.g. addition of antibiotic, amlodipine) or if other co-factors such as hypothyroidism emerge
    • Resolve quickly and usually within 1 month of statin withdrawal
  • Ask the patient what they think may have caused their symptoms and the reason why they think this may be the case
  • Ask the patient to rate the severity of their pain on a scale of 1 to 10, as well indicate how this affects their daily life
  • What has happened if the patient has omitted statin doses?
  • Exclude recent strenuous or unaccustomed exercise
  • Exclude recent trauma or exposure to infectious agents (e.g. influenza)—generalised muscle symptoms related to viral illness tend not to last more than a few days—generalised muscle symptoms related to viral illness tend not to last more than a few days
  • Consider if the patient is drinking excessive amounts of alcohol (ethanol muscle toxicity)
  • If the patient describes ‘cramps’, these are more likely to be simple nocturnal cramps but rarely magnesium deficiency could be considered
  • Exclude the myalgic side-effects of other drugs, e.g. bisphosphonates, raloxifene, or diuretics
  • During the physical examination ask the patient where the pain is localised and assess if this is a generalised symmetrical muscle pain, tenderness, or weakness that is typical of myalgia and present for 3 or more days
  • Take blood samples for assessment of renal, liver, and thyroid function tests as well as CK level:
    • Is the CK level raised compared with prior levels (if baseline values are available) or with normal population values if prior test results are not available? (In patients whose usual CK is much lower than the laboratory ULN, multiples of the increase from baseline may be a more sensitive indicator of muscle damage)
    • Does the patient have a chronic disease such as untreated hypothyroidism or liver disease that might be increasing the risk of myalgia?
    • Consider the differential diagnosis of myalgia (see below)
    • How acceptable are the symptoms to the patient?

The primary care management of myalgia in patients who are taking statins continued

Diagnosis and differential diagnosis

  • Risk factors for myalgia in patients taking statins:
    • Nutrients or drugs metabolised by cytochrome P450
    • Higher statin dose
    • History of muscle disorders such as fibromyalgia, and/or rare muscle disorders, or a history of myalgia
    • Chronic kidney disease (graded as 3, 4, or 5)
    • Liver disease
    • Untreated hypothyroid disease
    • Multiple co-morbidities and polypharmacy
    • Alcohol excess
    • Increasing age
    • Being female
    • Diabetes
    • Frailty
    • Low body mass index (BMI) or small body frame
    • Major surgery
    • Severe trauma
    • Acute infection
    • Genetic factors such as polymorphisms of cytochrome P450 isoenzymes or drug transporters*

*This is a complex area and it is not always easy to identify those patients at increased risk

Note: This list is not exhaustive and other conditions may increase the risk of myalgia when patient is also taking a statin.

Management of myalgia

  • The management pathway shown in Figure 1 should be referred to, but for each patient the individual risk/benefit relationship should be determined
  • Statin treatment should be discontinued immediately if the myalgia is severe and/or the CK level is ≥5 x ULN or if the GP is concerned about the patient developing myositis
  • Is the myalgia related to the dose of statin?
  • Consider patient risk factors, especially the possibility of drug or nutrient interactions (see Box 1, below)
  • Screen the patient for kidney, liver, and thyroid disease:
    • If the patient’s renal function significantly deteriorates then the statin should be stopped, other treatments reviewed, and specialist advice sought
    • If the liver function tests show aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × ULN on two occasions, or if there is new evidence of liver disease then stop the statin and investigate as appropriate
    • Untreated hypothyroidism should be managed appropriately
    • If concerned about the patient’s condition, the statin should be discontinued while waiting for the blood test results
    • Where possible, comparisons should be made with previous laboratory test results
  • If the CK level is within the normal range or up to 3 × ULN then it is reasonable to continue statin treatment on the same or a different statin provided the degree of myalgia is acceptable to the patient. If symptoms are not acceptable, the statin dose can be reduced, or the statin can be switched, or the statin can be stopped for 2 months before re-challenge
  • If the CK level is between 3–5 × ULN, the patient should be monitored closely for symptoms but it is safe to continue statin treatment. Re-test CK level after a strenuous activity-free 48-hour period to see if levels have risen further, remain elevated, or have returned to the normal range:
    • If the CK is still elevated (3–5 × ULN after 48 hours), the statin can be continued, reduced, switched, or stopped then re-challenged depending on the symptoms experienced by the patient
    • CK levels should be re-tested 1 month later and the patient should be referred to a specialist if CK is still 3–5 × ULN
  • Be cautious when combining statins with fibrates and, if this is unavoidable, use a low dose of statin to start with and uptitrate if necessary. Fenofibrate is preferred; do not use gemfibrozil with a statin
  • Avoid using the maximum recommended dose of statin unless there is a compelling reason to do so (for example, a post-myocardial infarction patient may receive 80 mg atorvastatin if they can tolerate it)
  • If antibiotics that inhibit CYP P450 3A4 are required, in the absence of evidence-based advice, stop the statin if it is metabolised via the CYP P450 3A4 system for the duration of antibiotic therapy. If the antibiotic is to be administered long-term, give the lowest dose of that statin or change to a statin that is not metabolised via this pathway, e.g. pravastatin, rosuvastatin, or fluvastatin, for the duration of the antibiotic treatment

Box 1: Drugs that may increase the risk of myositis in patients taking a statin

  • Fibrates
  • Erythromycin and other macrolide antibiotics
  • Calcium channel blockers such as amlodipine, diltiazem, or verapamil
  • Amiodarone
  • Cyclosporin
  • HIV protease inhibitors
  • Azole antifungals
  • Excessive quantities of grapefruit juice
  • Red rice yeast (equivalent to 20–40 mg lovastatin)
  • Niacin
  • Fusidic acid

The primary care management of myalgia in patients who are taking statins continued

Figure 1: Algorithm for the primary care management of myalgia in patients taking statins

The primary care management of myalgia in patients who are taking statins continued

Pharmacological options: statins

  • Table 1, below shows properties of the five statins in use in the UK
  • If a patient is not able to tolerate one statin, they may be able to tolerate re-introduction of a lower dose of the initial statin after a period of withdrawal, or a different statin:
    • If the patient has a perceived side-effect that is potentially related to their statin, the statin should be discontinued for 3–4 weeks before being re-introduced at a low dose with uptitration if necessary
    • CK should be checked 3–4 weeks after the statin has been discontinued, and then CK can be monitored when the statin is reintroduced
    • If switching statins in a patient who presented with statin-associated myalgia, start with a low dose of the new statin (this is usually the lowest licensed dose), but be prepared to titrate upwards for clinical benefit
  • Choice of statin should be based on (see Table 1, below):
    • Best practice and the potential for drug interactions due to the CYP P450 3A4 system—this is particularly relevant for simvastatin and atorvastatin. Alternatives such as pravastatin, fluvastatin modified release (XL), or rosuvastatin should be considered
    • Efficacy in reducing LDL-C (rosuvastatin > atorvastatin > simvastatin > pravastatin > fluvastatin)
    • Cost of the statin (simvastatin < atorvastatin < pravastatin < rosuvastatin < fluvastatin modified release)
  • If a non-CYP P450 3A4 statin is not tolerated in the first instance, treatment with any other statin should be considered, starting at a low dose—the order in which the various statins are trialled should be made according to the criteria listed above
  • Other considerations include:
    • Fluvastatin XL does not reach the systemic circulation as it acts within the liver and is essentially all removed by the liver in first pass metabolism meaning very little gets into the blood stream. This has potential benefits in patients who may be taking other drugs that might interact and may explain its lower rate of reported adverse effects
    • Atorvastatin can be used at all stages of chronic kidney disease (CKD 1–5); simvastatin and fluvastatin should only be used at CKD stages 1–3 without dose adjustment; and rosuvastatin should only be used at CKD stage 1–2 without dose adjustment
  • Approximately two-thirds of the effect of a statin is seen at the starting dose and there is limited extra benefit from increasing the dose:
    • All statins are efficacious and only a 5%–6% further reduction in LDL-C is seen with doubling the dose
  • Non-daily dosing (e.g. giving a low dose every second or third day) with statins has shown safety, tolerability, and efficacy benefits in patients who are unable to tolerate a daily dose of statin.This mainly applies to long half-life statins (atorvastatin and rosuvastatin). Care should be taken to comply with the licensed indication for the statin wherever possible
  • Statins are extremely cost-effective and if a patient has their statin withdrawn because of myalgia, another statin may be a good option even if the individual cost of the statin is more:
    • Atorvastatin is now off patent and its cost has already been reduced
    • Switching statins is justifiable in high-risk patients and is cost-effective
  • If two statins have been tried and the patient has not been able to tolerate these agents, continue to try other statins or consider seeking specialist advice

Table 1: Key properties of statins

Parameter Atorvastatin
(10–80 mg)
Fluvastatin
(20–80 mg)
Pravastatin
(10–40 mg)
Rosuvastatin
(5–40 mg)
Simvastatin
(10–40 mg)
LDL-C lowering efficacy (%) 35–50 20–35 20–30 40–55 25–40
Liver metabolism pathway Cytochrome P450 3A4 Cytochrome P450 2C9 Sulfation Cytochrome P450 2C9/19 Cytochrome P450 3A4
Half life (hours) 14–21 <1 1.8 20 3

Alternative pharmacological options

  • Ezetimibe—NICE recommend that ezetimibe can be used as monotherapy in the situation where a statin is contraindicated or not tolerated. Ezetimibe can be used with a statin when target cholesterol levels are not achieved, particularly if a person is unable to try higher doses of the statin because it is likely to cause side-effects
  • Bile acid sequestrants
  • Fibrates—the working party group feels these should be considered last line when no other options exist

Non-pharmacological therapy after statin discontinuation due to myalgia

  • Non-pharmacological therapies should always be offered to patients who require CVD risk protection including those who are unable to tolerate or unwilling to accept statin treatment after referral to a specialist
about this working party guideline…
sponsor— This working party guideline was developed by MGP Ltd, the publisher of Guidelines and the working party was convened by them. AstraZeneca was able to review the scope and title for technical accuracy, with final decisions resting with the Chair. The content is independent of and not influenced by AstraZeneca who checked the final document for technical accuracy only.
working party members— George Kassianos (Chair, General Practitioner; Fellow of the European Society of Cardiology), Jane Armitage (Professor of Clinical Trials and Epidemiology), Paramjit Gill (General Practitioner), Jonathan Morrell (General Practitioner), John Reckless (Consultant Endocrinologist), Adie Viljoen (Consultant Chemical Pathologist and Lipidologist)
further information— call MGP Ltd (01442 876100) for further information and a copy of the full guideline
May 2013

First included: June 2013.

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