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Multiple sclerosis: drugs for symptomatic treatment

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Claire Reed
BSc(Hons) ClinDip
MRPharmS
Neurosciences
Pharmacist
Queen’s Medical Centre
Nottingham, UK
E:claire.reed@mail.qmcuh-tr.trent.nhs.uk

Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system (CNS), characterised by inflammation and demyelination of white matter in the brain
and spinal cord.(1) Multiple areas of scar tissue (sclerosis) form along the nerve fibres, slowing or blocking the transmission of signals to and from the brain and spinal cord, so that various functions, including movement and sensation, may be lost.(2) The disease therefore is manifested in physical symptoms (often with relapses and disability progression – see Table 1), CNS inflammation and cognitive dysfunction. There is great inter- and intrapatient variability of symptoms.

[[HPE08_table1_40]]

Although there are no clinical symptoms pathognomic for MS, some manifestations are relatively specific, such as optic neuritis, internuclear ophthalmoplegia, diurnal fatigue, Lhermitte’s sign (electric shock sensation upon neck flexion), partial transverse myelitis, acute urinary retention and Uhthoff’s phenomenon (worsening of symptoms associated with a small increase in body temperature).(4)

Treatment of symptoms
The treatment of a chronic neurological disease such as MS is difficult due to its fluctuating nature. As response to treatment is often unpredictable, it is generally best to start with a low dose and titrate upwards guided by therapeutic and adverse effects.

Spasticity
Spasticity plays a major part in the loss of mobility. With disease progression, spasticity and spasms increasingly affect the muscles of flexion, causing pain and making nursing difficult. Bed sores may result from and worsen these spasms.(3)

Baclofen
Baclofen is the drug of choice for spasticity. It is a GABA derivative and acts as an antispasmodic agent at a spinal level. It is effective, but its use may be limited by sedation or increasing weakness. A starting dose of 5mg three times a day is recommended. Maximising the bedtime dose may be beneficial. Low starting doses should always be used in elderly patients, who may be more susceptible to the sideeffects on initiation. A daily dosage of more than 100mg given in three to four divided doses is not recommended, unless under close supervision. Stopping baclofen abruptly may cause anxiety and confusional states, hallucinations, psychotic, manic or paranoid states, and tachycardia. A rebound worsening of spasticity may also occur.(5)

In severe chronic spasticity, poorly responsive to oral therapy, baclofen may be administered intrathecally via a pump. This is implanted in the chest or abdominal wall tissue. A catheter connects it to the intrathecal space. The main adverse effects are pump malfunction, kinking or dislodgment of the catheter. The reservoir in the pump must be refilled aseptically by trained and qualified personnel, as care is needed to avoid discharging the contents of the catheter into the intrathecal space.

Tizanidine
Tizanidine is an α2-adrenergic receptor agonist that acts at supraspinal and spinal levels within the CNS. It is used as an alternative to baclofen, especially if baclofen use is limited by adverse effects, as it tends to produce less muscle weakness. Treatment starts at a daily dosage of 2mg, increasing according to response at intervals of three to four days in increments of 2mg. It has a relatively short duration of action, and therefore the daily dosage is usually given in three or four divided doses. A total daily dosage of 36mg should not be exceeded, although it is not usually necessary to exceed 24mg daily.(6)

Benzodiazepines
Diazepam and clonazepam may also be used to treat spasticity. Their usefulness is limited by sedation and dependency, but they may be of most use at night, where sedation can be of help.
 
Dantrolene
Dantrolene has a direct action on skeletal muscle and produces fewer central adverse effects. However, it may cause muscle weakness, which is poorly tolerated. An initial dosage of 25mg is recommended, increasing to a maximum of 100mg four times a day at weekly intervals to determine the patient’s response. Therapeutic effect may take a few weeks to develop, but in light of the hepatotoxic effects of long-term use, if there is no benefit after 45 days, treatment should be discontinued.(7)

Incoordination and cerebellar tremor
This can lead to disability due to loss of limb function, even where strength is maintained. Minor tremor may respond to weights on the affected limb. Many drugs have been tried, with limited success. These include: isoniazid (600–1,200mg daily) given with pyridoxine to prevent peripheral  europathy;(8,9) ondansetron, although benefit has been shown only with intravenous use;(10,11) and β-blockers (eg, propranolol 20–40mg three times daily) and clonazepam (0.5–2mg once daily to four times daily).

Fatigue
Fatigue is a common complaint, affecting the majority of patients with MS. In general, fatigue does not respond well to pharmacological intervention, so lifestyle adaptations are
usually necessary. Drugs that have been tried include: amantadine 100mg twice a day; pemoline 18.75–37.5mg twice daily (no longer available in the UK: it is potentially hepatotoxic, and patients receiving it should have regular liver function tests); fluoxetine 10–40mg a day; methylphenidate 10–20mg once daily to twice daily; and 4-aminopyridine and 3,4-diaminopyridine.(12–16)
 
Pain
Up to 32% of MS patients regard pain as their most severe symptom. MS-related pain is usually neuropathic, and treatment is the same as for the general population – using amitriptyline, carbamazepine, gabapentin, etc. Cannabis and its pharmacological derivatives are currently undergoing a number of trials in MS. These are reported to alleviate spasticity, pain and tremor.(17)

Bladder dysfunction
Urinary symptoms of frequency, urgency and urge incontinence are common in MS, and occur as a result of detrusor instability and spasm. With disease progression, loss of detrusor tone causes urinary retention, frequency and incontinence. Oxybutynin (2.5–5mg once daily to three times daily) is an anticholinergic agent that also acts as an
antispasmodic on the smooth muscle of the bladder, which helps to inhibit bladder contraction. Tolterodine (2mg twice daily), a competitive cholinergic receptor antagonist with bladder selectivity, may also be used. Both arecontraindicated in urinary retention.

Desmopressin (20–40mg before bed) may be used for the treatment of nocturnal enuresis.

Bowel dysfunction
Constipation is a common problem in those with immobility; adequate fluid intake and a high-fibre diet are necessary, as well as the occasional use of stimulant laxatives.

Sexual dysfunction
Erectile dysfunction is common in male patients with MS. This may be treated with sildenafil,(18) or prostaglandins such as alprostadil.

Mood disorders
Depression is more common in MS patients than in the general population.(19) It usually responds to standard antidepressant treatment. Several of the treatments used in MS may themselves cause depression and could be altered if appropriate; these include beta interferons, baclofen and corticosteroids.

Summary
Although there are disease-modifying agents available, they have not been shown to prevent disease progression completely. Therefore symptomatic treatment, along with supportive measures and rehabilitation, is a major part of the treatment of MS.

References

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  2. Clegg A, Bryant J, Milne R. Disease modifying drugs for multiple sclerosis: a rapid systematic review. Health Technol Assess 2000;4(9).
  3. Richards RG, et al. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models. Health Technol Assess 2002;6(10).
  4. Best practice of medicine. Available from URL: http://www.merck.praxis.md
  5. Lioresal. Summary of product characteristics. Available from URL: http://emc.vhn.net
  6. Zanaflex. Summary of product characteristics. Available from URL: http://emc.vhn.net
  7. Dantrium. Summary of product characteristics. Available from URL: http://emc.vhn.net
  8. Morrow J, et al. Isoniazid and action tremor in multiple sclerosis. J Neurol Neurosurg Psychiatry 1985;48:282-3.
  9. Hallett M, et al. Controlled trial of isoniazid therapy for severe postural cerebellar tremor in multiple sclerosis. Neurology 1985;35:1374-7.
  10. Rice GP, et al. Ondansetron, a 5-HT3 antagonist, improves cerebellar tremor. J Neurol Neurosurg Psychiatry 1997;62:282-4.
  11. Rice GP, et al. Ondansetron versus placebo for disabling cerebellar tremor: final report of a randomised clinical trial. Ann Neurol 1999;46:493.
  12. Branas P, et al. Treatments for fatigue in multiple sclerosis: a rapid and systematic review. Health Technol Assess 2000;4(27).
  13. Krupp LB, et al. Fatigue therapy in multiple sclerosis: results of a double blind, randomised, parallel trial of amantadine, pemoline and placebo. Neurology 1995;45:1956-61.
  14. Weinshaker BG, et al. A double blind, randomised, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology 1992;42:1468-71.
  15. Polman CH, et al. 4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety. Arch Neurol 1994;51:292-6.
  16. Sheean GL, et al. An open labelled clinical and electrophysiological study of 3,4-diaminopyridine in the treatment of fatigue in multiple sclerosis. Brain 1998;121:967-75.
  17. Williamson E, Evans F. Cannabinoids in clinical practice. Drugs 200;60:1303-14.
  18. British national formulary. Available from URL: http://www.bnf.vhn.net
  19. Whitlock FA, Siskind MM. Depression as a major symptom of multiple sclerosis. J Neurol Neurosurg Psychiatry 1980;43:861-5.


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