30. Adjuvant analgesics. Drugs used to treat gout. Centrally-acting muscle relaxants

Last updated on June 17, 2019 at 20:15

Adjuvant analgesics for neuropathic pain

Neuropathic pain is caused by damage to peripheral or central pathways. This pain is not easily treated as it responds poorly to conventional analgesics like NSAIDs, and even to opioids. Other drug types are necessary.

The following drugs are effective for treating neuropathic pain:

  • Tricyclic antidepressants
    • Amitriptyline
    • Nortriptyline
  • Antiepileptics
    • Gabapentin
    • Carbamazepine
    • Lamotrigine
  • Local anaesthetics
  • Capsaicin
  • Nabiximols (cannabis preparations)
  • Glucocorticoids

Nabiximols are described in “centrally acting muscle relaxants”. The other drugs have been described in other topics.

Capsaicin

Capsaicin is the molecule in spicy foods that make them spicy.

Indications:

Neuropathic pain.

Mechanism of action:

Capsaicin binds to receptors in nociceptive nerve endings and reversibly damages them, preventing them from causing neuropathic pain.

Dosing:

It’s applied as a dermal patch. It should be placed on the painful area for one hour. It takes 1 – 2 weeks for the analgesic effect to develop, but it lasts for up to 3 months.

Side effects:

When placing the patch there is a painful response, but this can be alleviated with local anaesthetics.

Gout

Gout is a condition caused by precipitation of sodium urate crystals in soft tissue, joints and kidneys. It’s always related to an increase in uric acid (urate) levels in the body, either due to a primary genetic defect in uric acid secretion or due to any other condition that causes accumulation of uric acid, like:

  • Massive cell destruction – as cells release purine nucleotides that are metabolised into uric acid
    • Often during chemotherapy of malignant tumors
  • Reduced excretion of uric acid
    • Renal failure
    • Thiazide or loop diuretics
  • Ethanol

Xanthine oxidase is the most important enzyme in this disease, as it’s involved in the breakdown of xanthine and hypoxanthine into uric acid. Hypoxanthine and xanthine are water-soluble, but uric acid is not.

Treatment:

Treatment involves diet low in purines, abstinence from alcohol and adequate fluid intake. Pharmacological treatment involves:

  • Uricostatic agents – drugs that reduce the formation of uric acid
    • Allopurinol
    • Febuxostat
  • Uricolytic agents – drugs that cleave uric acid
    • Rasburicase
  • Uricosuric agents – drugs that reduce renal reabsorption of uric acid
    • Probenecid
    • Lesinurad

Arthritic attacks are treated with anti-inflammatory drugs like NSAIDs, colchicine and glucocorticoids.

Uricostatic drugs

Allopurinol and febuxostat are the important uricostatic drugs. The former is the first choice.

During the first few weeks NSAIDs should be co-administered to prevent gouty attacks.

Indications:

Prophylaxis for gout. Febuxostat is used in cases where allopurinol is not tolerated.

Mechanism of action:

Allopurinol is a competitive inhibitor for xanthine oxidase. It’s broken down into oxipurinol, which non-competitively inhibits the same enzyme.

Febuxostat is a non-competitive inhibitor for xanthine oxidase.

These drugs reduce the production of uric acid and cause hypoxanthine and xanthine to accumulate instead. These compounds are water-soluble and will be excreted by the kidney.

Interactions:

These drugs decrease the metabolism of azathioprine and mercaptopurine, as these are broken down by xanthine oxidase.

Side effects:

Gastrointestinal disturbances.

These drugs may precipitate a gouty attack in the first weeks of treatment. Co-administering NSAIDs or colchicine can prevent this.

Uricolytic drugs

The only important uricolytic drug is rasburicase. During the first few weeks NSAIDs should be co-administered to prevent gouty attacks.

Indications:

Prophylaxis for gout. Used in treatment-resistant cases of gout.

Mechanism of action:

Rasburicase is a recombinant form of urate oxidase, an enzyme that breaks down uric acid into water-soluble compounds like allantoin.

Dosing:

Intravenous infusion.

Side effects:

Allergic reactions. This drug may precipitate a gouty attack in the first weeks of treatment. Co-administering NSAIDs or colchicine can prevent this.

Uricosuric drugs

The most important drugs here are probenecid and lesinurad. During the first few weeks NSAIDs should be co-administered to prevent gouty attacks.

Indications:

Prophylaxis for gout.

Mechanism of action:

These drugs inhibit the transporter URAT1 in the proximal tubule, which preforms reabsorption of uric acid. This causes less uric acid to be reabsorbed and more to be excreted.

Side effects:

The increased excretion of uric acid may increase the risk of urate urolithiasis. This can be prevented by increasing fluid intake.

These drugs may precipitate a gouty attack in the first weeks of treatment. Co-administering NSAIDs or colchicine can prevent this.

Colchicine

NSAIDs are preferred over colchicine to treat acute gouty attacks because they have less side effects.

Indications:

Acute gouty attacks.

Mechanism of action:

Colchicine inhibits the polymerization of tubulin into microtubules, which reduces the chemotaxis and phagocytic activity of neutrophils. It also inhibits some functions of T cells.

This decreases the inflammatory response seen during gouty attacks.

Dosing:

Oral or IV.

Contraindications:

Should be used with care in people with liver or renal failure.

Side effects:

Gastroenteritis, myopathy, teratogenicity.

Centrally acting skeletal muscle relaxants

These drugs act on the CNS to reduce pathologically increased muscle tone, without compromising voluntary muscle contractions (like peripheral muscle relaxants do). This is relevant in two cases:

  • Spasticity – resistance to movement, involuntary muscle spasms and enhanced stretch reflex
    • Caused by a lesion of the upper motor neuron, which regulate the stretch reflex
  • Acute muscle spasms

The following drugs are the most important here:

  • Baclofen
  • Nabiximols (cannabis extract)
  • Benzodiazepines
  • Tizanidine
Centrally acting agents used in spasticity and muscle spasms

The important drugs here are baclofen, nabiximols, benzodiazepines and tizanidine.

Indications:

Spasticity associated with stroke, cerebral palsy, multiple sclerosis. Muscle spasms for any reason.

Mechanism of action:

Baclofen is a GABAB receptor agonist. Benzodiazepines bind to an allosteric site on GABAA receptors, stimulating them. Stimulation of GABA receptors inhibits the stretch reflex, which reduces muscle tone and spasticity.

Nabiximols bind to and activate cannabinoid receptors, which inhibit the stretch reflex.

Tizanidine is an α2 receptor agonist which inhibits the stretch reflex.

Peripherally acting agents used in spasticity and muscle spasms

Dantrolene and botulinum toxin are also used to treat spasticity.

Mechanism of action:

Dantrolene blocks the ryanodine receptor, which the release of Ca2+ from the sarcoplasmic reticulum.

Botulinum toxin irreversibly inhibits release of acetylcholine in the neuromuscular junction.

Dosing:

Dantrolene is given orally or IV. Botulinum toxin is injected into muscles.


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29. Non-steroidal antiinflammatory drugs. Drugs other than aspirin or paracetamol

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31. Drugs used in the treatment of peptic ulcer

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