Locomotor system

Locomotor system

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Treating musculoskeletal and connective tissue disorders depends on the severity and cause of symptoms. Occasional pain can be controlled with exercises in combination with over-the-counter analgesics such as acetaminophen, and anti-inflammatories such as ibuprofen or other non-steroidal anti-inflammatory drugs (NSAIDs). Advanced conditions require prescription medications, which can be prescribed alongside physical and occupational therapy.

Several of the main drug classes used to treat these conditions are included in the topics below.

NSAIDs for musculoskeletal conditions

There are about 20 different nonsteroidal anti-inflammatory drugs (NSAIDs) available. Some, such as aspirin and ibuprofen, are widely available over-the-counter (OTC). Others are only available on prescription. NSAIDs are the most frequently used medicines for symptomatic relief in osteoarthritis (OA), the most common form of arthritis, and are often prescribed to rheumatoid arthritis (RA) patients.

NSAIDs are usually effective for a few hours, but some are available in modified-release formulations to prolong their effective period. They can be used in combination with paracetamol (acetaminophen) or compound analgesics such as co-codamol if necessary.

NSAIDs should however be used with caution as they all pose the risk of side-effects, such as stomach ulcers, gastrointestinal bleeding, kidney failure, heart attacks, and strokes. Aspirin and naproxen are moderately more suitable for patients at risk of heart disease or stroke. Should long term use be warranted co-administration with a proton pump inhibitor (e.g. omeprazole or esomeprazole) to help protect against gastro-intestinal damage is advised.

Below is a short list of some of the more commonly prescribed NSAIDs used for symptomatic relief in rheumatic, musculoskeletal and soft tissue conditions. Here we focus on use in these conditions and do not discuss other licensed indications for these drugs.

Ibuprofen is licensed for controlling pain and inflammation in rheumatic disease and other musculoskeletal disorders and soft-tissue injuries. Ibuprofen can be used to treat juvenile idiopathic arthritis (JIA), but not in infants under 3 months (or with body weight <5kg). Ibuprofen is available OTC, as oral tablets (immediate and modified-release) and in topical gels. Ibuprofen is low-risk for causing stomach ulcers.

Aspirin treats symptoms of mild to moderate pain. Available OTC.

Naproxen is licensed for symptomatic relief in rheumatic disease, musculoskeletal disorders and acute gout. In the UK it is a prescription medicine in relation to the mentioned indications (but is available OTC for primary dysmenorrhoea).

Celecoxib is the only COX-2 selective NSAID on the market. It is a prescription only medicine licensed for treating the symptoms of pain and inflammation in OA and RA, and for the treatment of ankylosing spondylitis.

Diclofenac and indomethacin are prescription only NSAIDs, suitable for treating pain and inflammation in rheumatic disease, other musculoskeletal disorders and acute gout. Indomethacin is high-risk for causing stomach ulcers.

Mefenamic acid is also available on prescription to treat pain and inflammation in OA and RA.

Disease-modifying anti-rheumatic drugs (DMARDs) (under construction)

Different types of arthritis (rheumatic disease) are treated with different drugs. The aim of the clinician is to prescribe drugs which improve symptoms and, where possible, slow or halt progress of the condition. As their name suggests, disease-modifying anti-rheumatic drugs (DMARDs) offer benefit via the latter mechanism. Full therapeutic response to DMARDs may take several months to become evident. Early intervention with DMARD therapy is recommended to control the signs and symptoms of rheumatic disease and to limit joint damage.

There are two main categories: conventional DMARDs and biological therapies. This topic covers conventional DMARDs, biological therapies are described in the Biological DMARDs topic.

Conventional DMARDs include:

Methotrexate is an oral medication prescribed for moderate to severe RA.

Gold (as sodium aurothiomalate) is given by deep intramuscular injection for active progressive RA. This is a long-term treatment, requiring regular dosing up to 5 years post-complete remission. Second courses of gold are not usually effective if the patients suffers a complete relapse.

Penicillamine has a similar action to gold. Penicillamine should be discontinued if there is no improvement within 1 year.

Sulfasalazine is prescribed for active RA on expert advice.

Hydroxychloroquine is prescribed for active RA on expert advice. 

 

Because of their toxicity, these next immunosuppressants are only used for RA when patients have not responded to other DMARDs:

Ciclosporin, a calcineurin inhibitor: only prescribed for severe active RA when conventional second-line therapy is inappropriate or ineffective.

Leflunomide is a pyrimidine synthesis inhibitor which regulates autoimmune lymphocytes. Used by specialist practitioners for treating moderate to   severe active RA and active psoriatic arthritis.

Cyclophosphamide: can be prescribed for RA with severe systemic manifestations and other connective tissue diesases (e.g. active vasculitis).

Azathioprine can be prescribed for RA that has not responded to other DMARDS.

Prescibers should consider co-morbidity and patient preference when choosing which DMARD (or combination of DMARDs) to prescribe. Whilst providing similar efficacy as intramuscular gold and penicillamine, methotrexate or sulfasalazine are often better tolerated. Gold and penicillamine can be effective in palindromic rheumatism. Methotrexate is generally prescribed alongside at least one other DMARD, and often short-term corticosteroid treatment for newly diagnosed RA.

Tofacitinib is an immunomodulating agent and DMARD with a novel mechanism of action. It selectively inhibits the activity of Janus kinase 3 (JAK3), a hematopoietic cell-restricted mediator of cytokine, growth factor, and interferon signalling via the JAK-STAT pathway. Inhibition of JAK3 appears to disrupt development and function of T, B, and NK cells. The FDA has approved tofacitinib for use in the management of moderate to severe active RA in patients who have shown an inadequate response or intolerance to methotrexate. Tofacitinib can be used alone or in combination with methotrexate or other nonbiologic DMARDs, although concomitant use with biologic DMARDs (e.g. adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, anakinra or rituximab), selective costimulation modulators (abatacept), and the anti-interleukin-6-receptor monoclonal antibody tocilizumab, is not recommended. Concomitant use with other immunosuppressive agents  (e.g. azathioprine or cyclosporine) is also not recommended. Serious, sometimes fatal infections (including cryptococcosis, pneumocystosis, tuberculosis and other mycobacterial infections, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infection) have been reported. Tofacitinib treatment should not be initiated in patients with active infections.

 

Biological DMARDs

Biological DMARDs take the form of monoclonal antibodies (mAbs) and recombinant fusion proteins which modulate cytokine levels via mechanisms which inhibit T and B cell activation, or by directly inhibiting pro-inflammatory tumour necrosis factor alpha (TNFα). All cytokine modulators must be used under specialist supervision.

Examples currently employed for anti-rheumatic therapy include:

Abatacept, a recombinant protein fusing the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to the modified Fc portion of human immunoglobulin G1 (IgG1). CTLA-4 is essential for T-cell co-stimulation. Abatacept acts as a T cell activation inhibitor and reduces active inflammation. Prescribed for moderate to severe active RA in patients unresponsive to other DMARDs, including methotrexate or TNFα inhibitors.

Tocilizumab, an anti-IL-6 receptor mAb, normally prescribed alongside methotrexate for patients with moderate to severe active RA unresponsive to other DMARDs or TNF inhibitors. Tocilizumab can be used as a monotherapy in patients intolerant of methotrexate. Use in the UK is covered by NICE guidance NICE TA375 and NICE TA247.

Rituximab, an anti-CD20 mAb designed to target surface CD20 on B-lymphocytes and classified as an anti-lymphocyte mAb. Rituximab can be prescribed for patients with severe active RA, whose disease has not responded adequately to other DMARDs, including one or more TNF inhibitors. Can also be prescribed for patients intolerant of other DMARDs. All anti-lymphocyte mAbs should be delivered by an experienced expert with immediate access to full resuscitation facilities. Due to their mechanism of action, this group of biologics can predispose patients to severe infection. In the UK use of rituximab infusion for RA is covered by NICE guidance (NICE TA195).

 

TNFα inhibitors

Etanercept, is a dimeric recombinant protein fusing the TNF receptor 2 to the Fc region of the human IgG1 antibody. This acts to bind TNF, removing it from the circulation, thereby reducing its pro-inflammatory effect. Indicated for moderate to severe active RA (with or without methotrexate) with an inadequate response to other DMARDs (see NICE guidance TA195), methotrexate naive severe, active, and progressive RA, active and progressive psoriatic arthritis inadequately responsive to other DMARDs (see NICE guidance TA103) and severe ankylosing spondylitis inadequately responsive to conventional NSAID therapy. Delivered by subcutaneous injection.

Adalimumab has a similar indication profile to etanercept, but may also be used to treat severe axial spondyloarthritis with objective signs of inflammation and without radiographic evidence of ankylosing spondylitis, in patients with an inadequate response to, or intolerance to NSAIDs. Delivered by subcutaneous injection.

Certolizumab pegol has a similar indication profile to adalimumab. Delivered by subcutaneous injection.

Golimumab has a similar indication profile to etanercept. Delivered by subcutaneous injection.

Infliximab was the first anti-TNFα mAb to be authorised for clinical use. It is licensed for active RA (with methotrexate) in patients with inadequate response to other DMARDs, and for patients with severe, active, and progressive RA who have not been treated with methotrexate or other DMARDs. Ankylosing spondylitis with severe axial symptoms and inadequate response to conventional therapy, active and progressive psoriatic arthritis not responding to DMARD therapy, and plaque psoriasis can also be treated with infliximab. Delivered by intravenous infusion.

 

Bone resorption inhibitors

Bisphosphonates

Bisphosphonates are a class of drugs used to prevent loss of bone mass in conditions characterised by excessive bone resorption which causes bone fragility, such as osteoporosis, Paget's disease of bone, bone metastasis and primary hyperparathyroidism. Mechanistically bisphosphonates bind to hydroxyapatite on bony surfaces, and are taken in to osteoclasts during bone resorption. Bisphosphonates act to disrupt osteoclast function and number (via apoptosis).

As bisphosphonates are poorly absorbed orally they should be taken on an empty stomach (with water) at least 30 minutes before food is ingested.

Safety information for all bisphosphonates includes being alert to the risk of bisphosphonate-induced atypical femoral fractures, with patients advised to report any thigh, hip, or groin pain whilst taking bisphosphonates. With intravenous bisphosphonates there is a very low risk of developing osteonecrosis of the jaw. Risk factors to consider include potency of the bisphosphonate, cumulative dose, duration and type of malignant disease, concomitant treatment, smoking, comorbid conditions, and history of dental disease. Patients should be advised to maintain good oral hygiene, attend routine dental check-ups, and report any dental mobility, or oral pain, swelling, non-healing sores or discharge during treatment. Benign idiopathic osteonecrosis of the external auditory canal has also been reported, primarily in patients receiving bisphosphonate therapy for >2 years. Risk factors for developing osteonecrosis of the external auditory canal include steroid use, chemotherapy, infection or ear operations.

There are two groups of bisphosphonate drugs:

Non-nitrogenous (simple) bisphosphonates are absorbed by osteoclasts and are broken down to metabolites that lead to the formation of inactive ATP molecules that cannot be used as a source of energy. Energy depletion then leads to osteoclast apoptosis. This sub-family of drugs cause more adverse effects than the nitrogenous bisphosphonates, so are prescribed less frequently.

  • Etidronate (etidronic acid- not available in the UK) is administered orally, being used to treat Paget's disease of bone and irregular bone growth due to hip fracture or spinal cord injury. Continuous use will lead to osteomalacia as etidronate prevents bone calcification. In light of this etidronate should be used infrequently and only for a short time and alternative bisphosphonates should be considered for treating osteoporosis.
  • Tiludronate (tiludronic acid- not available in the UK, discontinued in the US) is administered orally, being used to treat Paget's disease of bone.
  • Sodium clodronate (not available in the US) is delivered orally to treat osteolytic lesions and hypercalcaemia and bone pain associated with skeletal metastases in patients with breast cancer or multiple myeloma

Nitrogenous bisphosphonates bind to and inhibit farnesyl diphosphate synthase, an enzyme of the HMG-CoA reductase (mevalonate) pathway. Once absorbed by osteoclasts nitrogenous bisphosphonates inhibit production of isoprenoid precursors, leading to apoptosis.

Pamidronate (pamidronate sodium, pamidronic acid, ~100 times more potent than etidronate) is administered i.v. to treat hypercalcaemia of malignancy,  osteolytic lesions and bone pain in bone metastases associated with breast cancer or multiple myeloma and  Paget's disease of bone.

Alendronate (alendronic acid, ~500 times more potent than etidronate) is administerad orally for the treatment of postmenopausal osteoporosis, osteoporosis in men and for prevention and treatment of corticosteroid-induced osteoporosis in postmenopausal women not receiving hormone replacement therapy. Sometimes prescribed in combination with colecalciferol (vitamin D3).

Ibandronate (ibandronic acid, ~1000 times more potent than etidronate) is administered i.v. for the treatment of hypercalcaemia of malignancy, or orally to reduce bone damage in bone metastases in breast cancer and to treat postmenopausal osteoporosis.

Risedronate (risendronate sodium, ~2000 times more potent than etidronate) is delivered orally for the treatment of osteoporosis in men at high risk of fractures, postmenopausal osteoporosis to reduce risk of vertebral or hip fractures, Paget's disease of bone and for the prevention of postmenopausal osteoporosis (including corticosteroid-induced osteoporosis). Sometimes prescribed in combination with calcium and colecalciferol (vitamin D3).

Zoledronic acid (~10000 times more potent than etidronate) is delivered by i.v. infusion for the treatment of Paget's disease of bone, postmenopausal osteoporosis and osteoporosis in men (including corticosteroid-induced osteoporosis), hypercalcaemia of malignancy and to reduce bone damage in advanced malignancies involving bone.

 

Calcitonin

In normal physiology calcitonin is involved in calcium (Ca2+) and phosphorus metabolism, acting to lower blood Ca2+ levels and increase calcium and phosphate deposition in bone. Calcitonin protects against skeletal calcium depletion during periods of calcium mobilization (e.g. during pregnancy and lactiation).

In the clinic calcitonin salmon (peptide produced by recombinant technology or peptide synthesis) is used to treat hypercalcaemia of malignancy, osteitis deformans (Paget's disease of bone), for prevention of acute bone loss due to sudden immobility, and is used to treat postmenopausal osteoporosis in some countries.

 

Cinacalcet

Cinacalcet is a positive allosteric activator of the calcium-sensing receptor (CaSR) which potentiates the action of extracellular calcium by lowering the threshold for CaSR activation and leads to inhibition of parathyroid hormone (PTH) secretion and production. Decreased levels of PTH results in diminished osteoclast-driven bone resorption. Cinacalcet is prescribed for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on dialysis, primary hyperparathyroidism in patients where parathyroidectomy is inappropriate and hypercalcaemia in parathyroid carcinoma.

 

Raloxifene hydrochloride

Raloxifene is a selective estrogen receptor modulator (SERM) with estrogen-like effects on bone which reduce bone resorption and increase bone mineral density in postmenopausal women. Raloxifene is prescribed for the prevention and treatment of osteoporosis in postmenopausal women.

 

Denosumab

Denosumab is a monoclonal antibody which suppresses the activity of RANK ligand (RANKL), which normally promotes bone removal and resorption, but which becomes over active in many bone loss diseases. The drug is delivered by s.c. injection for the treatment of postmenopausal osteoporosis and men at increased risk of fractures, bone loss associated with hormone ablation in patients with prostate cancer at increased risk of fractures, giant cell tumour of bone that is unresectable and prevention of skeletal related events in patients with bone metastases from solid tumours.

Like the bisphosphonates, denosumab poses a risk of atypical femoral fractures, osteonecrosis of the jaw and hypocalcaemia.

 

Strontium ranelate

Strontium ranelate is a strontium(II) salt of ranelic acid, which acts as a "dual action bone agent" (DABA) which both increases new bone depostion by osteoblasts and reduces resorption by osteoclasts. Due to the reported risk of myocardial infarction, strontium ranelate is only recommended for treatment of severe osteoporosis in postmenopausal women or men at high risk for fracture in cases where other treatments are contra-indicated or not tolerated.

 

Hormone replacement for osteoporosis

Although other drugs are preferred as prophylaxis of postmenopausal osteporosis, hormone replacement therapy (HRT) can be considered when other therapies (bisphosphonates for example) are contra-indicated, not tolerated, or fail to produce clinical benefit. HRT is most effective in preventing postmenopausal osteoporosis if therapy is started in early menopause and is continued for up to 5 years (but note that bone loss resumes when HRT is withdrawn).  Women with early or surgical menopause are at high risk of developing osteoprosis and HRT can be given to these women, but should be discontinued once they reach the age at which the natural menopause would be expected (~50 years). If HRT is considered appropriate, the minimum effective dose should be prescribed for as short a duration as possible. Alternative treatments should be considered if osteporosis develops.

For women with a uterus combined estrogen/progestogen HRT is appropriate. For women without a uterus estrogen only HRT is suitable.

Somatotropin and growth hormone antagonists

Growth hormone (GH) replacement

Recombinant GH (somatotropin, peptide sequence identical to human pituitary growth hormone 1) is licensed to treat gonadal dysgenesis (of Turner syndrome) and GH deficiency (including growth failure in children- see NICE guidance TA188 in the UK). It is administered by s.c. injection and is available in injection devices and needle-free autoinjectors.

 

Modulation of GH activity

GH activity can be altered by the administration of somatostatin analogues or GH receptor antagonists.

Somatostatin analogues

In normal physiology somatostatin acts to inhibit production of several hormones, including GH and some gut hormones and controls release of hormones from the pancreas. Pharmacological analogues mimic somatostatin's effects in particular indications. In carcinoid tumours these drugs are used to inhibit secretory activity and reduce carcinoid syndrome symptoms such as flushing and diarrhea.

  • lanreotide is licensed to treat acromegaly, neuroendocrine tumours and thyroid tumours. Lanreotide can be used to manage unresectable advanced or metastatic gastroenteropancreatic neuroendocrine tumours of midgut, pancreatic or unknown origin where hindgut sites of origin have been excluded.
  • octreotide is licensed for symptomatic relief from carcinoid tumour related effects, for short-term treatment of acromegaly before surgery, or for longer-term treatment of tumours inadequately controlled by other treatment or post-radiotherapy whilst it takes full effect. In palliative medicine octreotide is licensed to reduce intestinal secretions and vomiting caused by bowel obstruction.
  • pasireotide is licensed to treat Cushing's disease in patients for whom surgery is inappropriate or has failed. This drug is used less often than lanreotide and octreotide.

 

GH receptor antagonist

GH receptor antagonists compete with endogenous GH for the receptor and inhibit proper GH signal transduction. One of the effects of GH receptor antagonism is a reduction in IGF-1 production and sectretion, and disruption of the GH/IGF-1 axis.

  • pegvisomant is a peptidic GH receptor antagonist licensed in the UK to treat acromegaly in patients with inadequate response to surgery and/or radiation and to treatment with somatostatin analogues. The peptide is conjugated with polyethylene glycol (PEGylated) to increase its circulating half-life.
     

 

 

Muscle relaxants

Muscle relaxants are a group drugs that act as central nervous system depressants which have overall sedative and musculoskeletal relaxant properties. Examples from many different drug classes have these effects, despite their different mechanisms of action. Muscle relaxants should preferably be prescribed short-term to reduce skeletal muscle spasms, provide relief from pain, and increase mobility of the affected muscles and should where appropriate be used together with rest and physical therapy as part of an overall recovery strategy.

There is very little research regarding which type of muscle relaxant is more effective. The choice of which medication to prescribe is therefore based on other factors such as the potential for abuse, possible drug interactions and adverse side-effects.

 

Some commonly used muscle relaxants are:

Baclofen is a centrally acting muscle relaxant licensed to treat muscle tightness and muscle spasms, including those related to spine injuries. The medication may be helpful in treating multiple sclerosis and stabbing nerve pain.

Methocarbamol is a carbamate type, centrally acting muscle relaxant prescribed to relieve acute muscle pain. It can also be used as adjunctive therapy to control the neuromuscular manifestations of tetanus.

Tizanidine is a centrally acting muscle relaxant prescribed to manage muscle spasticity. It is given to adults with multiple sclerosis and spinal cord injury and can be prescribed for children with cerebral palsy. It should not be prescribed alongside fluvoxamine or ciprofloxacin or to patients with liver disease.

Diazepam is a centrally acting muscle relaxant licensed to treat muscle spasms of varied aetiology, including muscle spasm in cerebral spasticity, postoperative skeletal muscle spasm and muscle spasm in palliative care (oral), acute muscle spasm (intramuscular injection, or by slow intravenous injection), tetanus (i.v. injection, infusion or nasoduodenal tube). This is in addition to its uses in anxiety management, alcohol withdrawal and controlling seizure disorders such as epilepsy). Use of diazepam is usually limited to 1-2 weeks due to its habit-forming potential. BNF Muscle spasm

Dantrolene acts within the skeletal muscle and is licensed for controlling chronic spasticity, including that related to spinal injuries. It is also used for conditions such as stroke, multiple sclerosis, and cerebral palsy. It can cause liver toxicity.

 

The following drugs are licensed in the US but not in the UK:

Chlorzoxazone is licensed to provide relief from discomfort caused by acute, painful, musculoskeletal conditions. It can cause liver problems.

Carisoprodol relaxes muscles and eases pain and stiffness caused by acute bone and muscle problems, as may be caused by an injury. It can be habit-forming, particularly if used in conjunction with alcohol or other drugs that have a sedative effect.

Cyclobenzaprine eases stiffness and pain from muscle cramps or spasms. Its chemical structure is related to that of some antidepressant medications, although it is not an antidepressant. Cyclobenzaprine is the safest muscle relaxant for use in pregnancy.

Metaxalone is prescribed to manage pain and muscle spasms from sprains, strains, and muscle injuries. Metaxalone is the least sedative muscle relaxant. It can be prescribed for children 13 and older for musculoskeletal conditions. It should not be prescribed to patients with a known history of drug-induced, hemolytic, or other anemias, and kidney or liver disease.