Muscle Pain (Myalgia): Causes

Pathogenesis (development of disease)

Pathogenesis depends on the cause of the disease.

Etiology (causes)

Biographic causes

  • Genetic burden
    • The likelihood of statin intolerance (statin-associated muscle pain (SAMS)) is increased if patients had two copies of the LILBR5 gene variants Asp247Gly (homozygous): Probability of CK increase was increased almost 1.81-fold (odds ratio [OR]: 1.81; 95% confidence interval ranged from 1.34 to 2.45), and that of intolerance was increased 1.36-fold even at low statin doses (OR: 1.36; 95% confidence interval ranged from 1.07 to 1.73; p = 0.013)
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: SLCO1B1
        • SNP: rs4149056 in the gene SLCO1B1
          • Allele constellation: CT (5-fold risk of myopathy with statin administration).
          • Allele constellation: CC (17-fold risk of myopathy with statin addition).
        • Mutations in the RYR1 gene may be the cause of myalgias with or without rhabdomyolysis.

Behavioral causes

  • Drug use
    • Heroin
    • Cocaine
  • Muscle overload or soreness

Disease-related causes

Blood, blood-forming organs – immune system (D50-D90).

Endocrine, nutritional and metabolic diseases (E00-E90).

  • Carnitine palmitoyl transferase deficiency (CPT1, CPT2) – most common autosomal recessive inherited disorder of lipid metabolism affecting skeletal muscle; most common cause of genetic myoglobinuria (symptomatology: after endurance performance, mild infections, stressful situations (eg. E.g. cold, lack of sleep), fasting and medication (ibuprofen), the symptoms of myoglobinuria, myalgia (muscle pain) and cramps occur.
  • Electrolyte disturbances
    • Hypokalemia (potassium deficiency)
    • Hypocalcemia (calcium deficiency)
    • Hypomagnesemia (magnesium deficiency)
    • Hypophosphatemia (phosphate deficiency)
    • Hyponatremia (sodium deficiency)
  • Hyperthyroidism (hyperthyroidism) – neuromuscular symptoms occur in up to 79% of patients with symptomatic hypothyroidism
  • Hypoadrenalism
  • Hypothyroidism (underactive thyroid gland)
  • Hyperparathyroidism (parathyroid hyperfunction).
  • Hypoparathyroidism (parathyroid hypofunction).
  • Glycogenoses such as McArdle syndrome – group of inborn errors of metabolism.
  • Hypoparathyroidism (hypothyroidism of the parathyroid gland).
  • Hypothyroidism (hypothyroidism)
  • Myoadenylate deaminase deficiency (synonyms: MAD deficiency, myoadenylate deminase deficiency, MADD) – most common genetic metabolic defect of skeletal muscle; autosomal recessive inheritance; clinical presentation: exercise-induced muscle weakness, myalgia and cramps; occurrence preferentially in muscle groups close to the trunk, such as upper arms and thighs.
  • Porphyria or acute intermittent porphyria (AIP); genetic disorder with autosomal dominant inheritance; patients with this disease have a 50 percent reduction in the activity of the enzyme porphobilinogen deaminase (PBG-D), which is sufficient for porphyrin synthesis. Triggers of a porphyria attack, which can last a few days but also months, are infections, drugs or alcohol. The clinical picture of these attacks presents as acute abdomen or neurological deficits, which can take a lethal course. The leading symptoms of acute porphyria are intermittent neurologic and psychiatric disturbances. Autonomic neuropathy is often in the foreground, causing abdominal colic (acute abdomen), nausea (nausea), vomiting or constipation (constipation), as well as tachycardia (heart beats: > 100 beats/min) and labile hypertension (high blood pressure).

Cardiovascular system (I00-I99).

Infectious and parasitic diseases (A00-B99).

Musculoskeletal system and connective tissue (M00-M99).

  • Becker muscular dystrophy – genetic muscle wasting.
  • Dermatomyositis – chronic systemic disease belonging to the collagenoses; an idiopathic myopathy (= muscle disease) or myositis (= muscle inflammation) with skin involvement, which often occurs paraneoplastic; myalgias in about 50% of cases.
  • Duchenne muscular dystrophy – genetically caused muscle atrophy.
  • Inclusion body myositis – neuromuscular disease.
  • Fibromyalgia (fibromyalgia syndrome) – syndrome that can result in chronic pain (at least 3 months) in multiple areas of the body
  • Interstitial myositis
  • Lupus erythematosus, systemic (SLE) – severe multi-organ disease; autoimmune disease in which there is formation of autoantibodies; it is one of the collagenoses.
  • Muscle injuries
    • Muscle contusion (muscle contusion)
    • Muscle contusion
    • Muscle tear
    • Muscle strain
  • Myofascial pain syndrome
  • Myopathies (muscle diseases) with enzyme defects as well as toxic myopathies (e.g., due to statins).
  • Myositis (muscle inflammation), caused by viruses such as Cocsackie virus or bacteria such as Staphylococcus or Borrelia.
  • Forms of myotonia such as myotonia congenita or paramyotonia congenita.
  • Forms of myotonic dystrophy (muscle diseases) such as myotonic dystrophy type 1 (Curschmann-Steinert) or proximal myotonic myopathy.
  • Osteoporosis (bone loss)
  • Panarteriits nodosa – collagenosis, which leads to thickening of the walls of blood vessels and thus to deficiency of blood flow.
  • Polymyalgia rheumatica (PMR; disease of the rheumatic type) – bilateral muscle pain and/or bilateral stiffness (> 1 hour).
  • Polymyositis – immunologically caused disease, which belongs to the collagenoses; myalgias in about 50% of cases.
  • Rhabdomyolysis – dissolution of striated muscle fibers.
  • Rheumatoid arthritis – chronic inflammatory multisystem disease that usually manifests as synovitis (inflammation of the synovial membrane). It is also called primary chronic polyarthritis (PcP).
  • Vasculitides (vascular inflammation).
  • Other degenerative myopathies (muscular dystrophies).

Psyche – nervous system (F00-F99; G00-G99)

  • Amyloid myopathy – muscle disease characterized by the deposition of various substances.
  • Chronic fatigue syndrome (CFS).
  • Depression
  • Drug addiction (heroin, cocaine)
  • Epilepsy equivalent
  • Guillain-Barré syndrome (GBS; synonyms: Idiopathic polyradiculoneuritis, Landry-Guillain-Barré-Strohl syndrome); two courses: acute inflammatory demyelinating polyneuropathy or chronic inflammatory demyelinating polyneuropathy (peripheral nervous system disease); idiopathic polyneuritis (multiple nerve disease) of spinal nerve roots and peripheral nerves with ascending paralysis and pain; usually occurs after infections
  • Isaacs-Mertens syndrome (neuromyotonia) – sudden onset of the disease, which is to severe permanent tension of the muscles.
  • Compression of the spinal cord / spinal nerves.
  • Meningitis (meningitis)
  • Motor neuron diseases1, 2
    • Amyotrophic lateral sclerosis (ALS; synonyms: Myatrophic Lateral Sclerosis or Motor Neuron Disease and Lou Gehrig’s Syndrome) – degenerative disease of the motor nervous system; progressive and irreversible damage or degeneration of nerve cells (neurons) occurs. The degeneration leads to increasing muscle weakness (paresis/paralysis), which is accompanied by muscle wasting (amyotrophy).
    • Poliomyelitis (polio).
  • Parkinson’s disease1 (shaking palsy)
  • Multiple sclerosis1 (MS)
  • Neuralgia – pain may occur in the area of spread of a sensitive nerve without a demonstrable cause.
  • Nerve root irritation syndrome1
  • Neuropathies1 (diseases of the peripheral nervous system) – diabetic, alcoholic.
  • Somatoform disorders such as chronic lower abdominal pain syndrome or in severe stress situations.
  • Spinal muscular atrophy – neurological disorder caused by nerve damage.
  • Stiff person syndrome1 – disease that leads to progressive stiffening of the trunk and limbs.
  • Radiculitis (nerve root inflammation).
  • Tabes dorsalis (neurolues) – late stage of syphilis in which there is demyelination of the spinal cord.

1Muscle cramps (Krampie)2Fasciculations.

Injuries, poisonings, and certain other sequelae of external causes (S00-T98).

  • Ciguatera intoxication; tropical fish poisoning with ciguatoxin (CTX); clinical presentation: diarrhea/diarrhea (after hours), neurologic symptoms (paresthesias, numbness of mouth and tongue; cold pain on bathing) (after one day; persist for long to years)
  • Coturnismus – life-threatening disease that can occur after eating quail (Coturnix coturnix); clustering in Mediterranean countries; within a few hours after the poultry meal, rhabdomyolysis/dissolution of striated muscle fibers occurs (usually sharp increase in creatinine kinase, CK), accompanied by very severe limb pain, and in approx. 10 to 40 % of cases to subsequent acute renal failure; therapy is purely supportive, i.e. adapted fluid and electrolyte management, alkalinization of the urine and forced diuresis (greatly increased urine production with the aid of diuretics and increased fluid intake) to promote myoglobin and toxin excretion. Note: Cooking and freezing also do not protect against this intoxication.
  • Rhabdomyolysis – dissolution of striated muscle fibers.

Medication

  • Antiarrhythmic drug (amiodarone)
  • Antibiotic
    • Penicillin
    • Sulfonamides
  • Antiepileptic drug (phenytoin)
  • Antihypertensive (enalapril, labetalol).
  • Antimalarials (artemether, chloroquine, hydroxychloroquine, lumefantrine).
  • Antifungals
    • Allylamines (terbinafine)
  • Antiparkinsonian drugs (levodopa)
  • Antiprotozoal agents
    • Analogue of the azo dye trypan blue (suramin).
  • Antiretroviral drugs
  • Arsenic trioxide
  • Beta blocker (metoprolol)
  • Β2-sympathomimetic (salbutamol)
  • Calcimimetic (etelcalcetide)
  • Chelating agent (deferasirox, deferoxamine, D-penicillamine, deferiprone).
  • Fibrates
  • Gout agents (colchicine)
  • Hormones
  • H2 antihistamines (H2 receptor antagonists, H2 antagonists, histamine H2 receptor anatgonists) – cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine.
  • Immunomodulator (tacrolism)
  • Immunosuppressive (cyclosporine)
  • Immunotherapeutics (interferon α)
  • Lipid-lowering agents
    • Cholesterol absorption inhibitor – ezetimibe
    • Fibrin acid derivatives (fibrates) – bezafibrate, clofibrate, fenofibrate, gemfibrozil
    • HMG-CoA reductase inhibitors (hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors; Statins)-atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) more frequently cause rhabdomyolysis (disintegration of striated muscle fibers/skeletal muscle as well as cardiac muscle) in combination with fibrates, ciclosporin (cyclosporin A), macrolides, or azole antifungals; Furthermore, statins lead to a decrease in endogenous coenzyme Q10 synthesis; frequency of myalgia in clinical practice is 10% to 20%The term statin myopathy is used when:
      • Symptoms occur within four weeks of starting statin use
      • They remit within four weeks after discontinuation of the drug, and
      • Recur upon re-exposure.

      Most important risk factor of statin-related myopathy is dose: 80 mg simvastatin: 20-fold higher myopathy risk than study participants with a daily dose of 20 mg; no significant risk differences emerged between 20 and 40 mg. Patients with rs4149056 in the SLCO1B1 gene with the allele constellation CT were 3 times more likely to have myopathy on a statin than patients with TT genotype.There are now also studies (double-blind randomized and open-label nonrandomized) that attribute statin-associated muscle symptoms to a nocebo effect. Note: The following drugs/substances increase the risk of myalgias/myopathies on statins: Danazol; fibrates; HIV-1 protease inhibitors (indinavir, amprenavir, saquinavir, nelfinavir, ritonavir); itraconazole, ketoconazole; cyclosporine; fibrates; HIV-1 protease inhibitors (indinavir, amprenavir, saquinavir, nelfinavir, ritonavir); Macrolide antibiotics (erythromycin, telithromycin, clarithromycin); nefazodone; verapamil; amiodarone; niacin (> 1 g); grapefruit preparations (There is no claim to completeness! )

  • Lithium
  • Monoclonal antibodies – imatinib, pertuzumab, trastuzumab.
  • Narcotic (propofol)
  • Opioid antagonists (nalmefene, naltrexone).
  • Phosphodiesterase-5 inhibitors/PDE5 inhibitors (avanafil, sildenafil, tadalafil, vardenafil).
  • Proton pump inhibitors (proton pump inhibitors, PPI, acid blockers).
  • Retionoids (acitretin, alitretinoin).
  • Selective prostacyclin IP receptor agonists (selexipag).
  • Antiviral (interferon alpha).
  • Cytostatic drug
    • Antimetabolites (methotrexate (MTX))
    • Hydroxyurea
    • Taxanes (paclitaxel)
    • Vincristine
    • Other cytostatic drugs (vincristine)

Environmental pollution – intoxications (poisoning).

  • Alcohol intoxication
  • Ciguatera intoxication; tropical fish poisoning with ciguatoxin (CTX); clinical picture: diarrhea (after hours), neurological symptoms (paresthesias, numbness of mouth and tongue; cold pain on bathing) (after one day; persist for long to years).
  • Heroin intoxication
  • Cocaine intoxication