Monthly Archives: November 2008

A Critical Review of the Pharmaceutical Culture

11/17/08

– with reference to the treatment of gout

Today, medications are available for the treatment of most illnesses. Patients are generally made aware of the potential complications and side effects of these drugs. The problems that frequently occur are complicated by the unknown factors, particularly with long-term multi-drug therapies.

No one can dispute the necessity of insulin for the control of diabetes or thyroxin for the treatment of hypothyroidism. At the same time, many conditions can be treated or even prevented, utilizing certain long-term measures or less dangerous therapeutic approaches. Aside from a balanced diet, the utilization of vitamins and supplements and the minimum of one-half hour of vigorous daily exercise, there are therapies available for the treatment of medical problems that can control or cure the pathological process involved, without risk.

This article focuses on a patient who was on a pharmaceutical regimen for the treatment of gout for a period extending over three years. The results were a number of undesirable consequences. The management of this patient clearly illustrates the need for re-evaluation of current medical practice. The drugs utilized were a combination of Allopurinol and Colchicine.

At Meditech over the past several years, we have demonstrated that Low Intensity Laser Therapy can completely resolve the symptoms and physical findings associated with gout. This usually occurs after two to four treatments over consecutive days. Patients may be inconvenienced with regard to travel and time, however this approach obviates all the dangers and complications involved with drug therapies.

Diagnosis

Gout has such a distinct clinical signature that it can generally be diagnosed by history and physical examination alone. Elevated serum urate (7 mg/dL) supports the diagnosis, but is not specific. It should be noted that 30% of patients have a normal serum urate level at the time of their first attack. The diagnosis of gout can be confirmed by histopathological analysis of the aspirated joint fluid, which will clearly demonstrate intracellular monosodium urate crystals. In addition, hypertension and renal insufficiency are typically present.4

Treatment

The initial treatment administered is generally directed to relieve the pain. This comprises the use of analgesics, NSAIDs, ice, etc. Drug therapy programs may include Allopurinol (xanthine oxidase inhibitor), Colchicine (microtubule polymerization inhibitor), corticosteroids, hormones or Probeniset (uricosuric). The intended effect is to lower uric acid levels and reduce inflammation in the joints.

Allopurinol is often prescribed to prevent recurrence, reduce the incidence of renal calculi and manage uric acid levels. Administration for an extended period of time may be required before the full effect of the drug is noted. Patients may also be advised to continue taking this medication even if they are asymptomatic. During the first few months, Allopurinol may cause an increase in attacks of gout, secondary to the inflammatory response. Colchicine is therefore often co-prescribed to minimize inflammation.

The potential side effects related to the administration of Allopurinol can be mild to serious.2 Skin rashes are common and may be evidence of an allergic reaction. Allopurinol may also cause irritation of the gastro-intestinal tract and produce drowsiness. A series of additional side effects have been reported, including hypersensitivity reactions manifested as hepatitis with symptoms of eosinophilia, dermal lesions, aplastic anemia and vasculitis. Some studies report that hypersensitivity leading to morbidity may be inordinately high in cases with prior liver or renal functional impairment. Gastrointestinal bleeding has also been reported. Discontinuation of Allopurinol is usually recommended to avoid progression of these complications.

Allopurinol is considered to be the drug of choice in treating and preventing gouty arthritis and instances of uric acid accumulation.6 Whereas this drug is generally deemed to be safe, hypersensitivity exists, primarily in patients with chronic renal insufficiency.2 In these cases, a significant increase in mortality rates has been observed. The mechanisms leading to complications are still under investigation, however there is evidence suggesting that complications may be due to bacterial infection or viral reactivation, such as cytomegalovirus or human herpes virus-6.7, 8 A chronic history of renal insufficiency often characterizes a state of immunodeficiency, manifested particularly by impaired T-cell mediated responses with lower than normal levels of CD4+ and CD8+ lymphocytes.

Colchicine is often prescribed in conjunction with Allopurinol as a potent anti-inflammatory. This approach usually limits attacks of gout9 which tend to increase for the first few months of Allopurinol administration. Biologically, Colchicine is a mitotic inhibitor, which affects tissues with high rates of cellular division and is lethal to cellular replication in general. Clinically, some therapeutic value can be derived from this drug as a chemotherapy agent and indeed, it may have a role to play in this area. In high doses, it can cause gastrointestinal and renal problems and may even cause paralysis. Colchicine also acts as an immunosuppressant and therefore relieves the pain and discomfort associated with attacks of acute gout. The drug is generally administered to individuals who may be at risk of developing gout and in patients with pre-existing chronic inflammatory conditions such as rheumatoid arthritis. Potential risk factors associated with Colchicine vary from mild to extreme and may elevate morbidity and mortality rates significantly.

The case histories outlined below, demonstrate the potential hazardous complications of a drug therapy programme:

1. A Gutiérrez-Macías et al. reported the case of an 80-year-old male with a history of chronic renal insufficiency, who was given 300 mg Allopurinol per day to control uric acid levels. At initiation of the drug programme the patient was asymptomatic. After six weeks of treatment, he developed loss of muscle strength, anorexia, fever, diarrhoea, jaundice, abdominal pain and dermal lesions, in addition to severe eosinophilia. Essentially, his immune system ceased to function. Immune suppressants (Prednisone) were insufficient to reverse the effects and due to deterioration of liver function, hepatic encephalopathy ensued and the patient expired.1

2. M. Arakawa et al. describe a 43-year-old man with a history of chronic renal insufficiency who was given an open-ended prescription of Allopurinol (100 mg qd). After the first month of therapy, he began to experience symptoms (malaise, elevated body temperature) and was admitted to hospital. Two weeks later, he had a high fever with skin rashes (erythema multiforme) and a drug reaction was suspected. The administration of Allopurinol ceased immediately but his status continued to deteriorate, resulting in renal failure and virtual destruction of the integumentary system. Extensive blood testing revealed the presence of Cytomegalovirus. Despite blood transfusions and resuscitory efforts the patient died.5

It is important to stress that although these cases were are not common, the rate of deterioration was rapid. Individuals with chronic renal or liver insufficiency appear to be most vulnerable to Allopurinol hypersensitivity reactions although the mechanisms responsible for these adverse events remain unclear.

Case Report – Meditech Clinic

A 66-year-old Caucasian male presented for treatment of a pre-gangrenous right lower extremity on September 10, 2008. He had been on daily insulin for several years; he was also taking Allopurinol and Colchicine daily over the past 3 years, for the prevention of gout. While on these medications, he had not had any acute attacks of gout. Over this period of time however, the patient developed renal failure in addition to progressive peripheral arterial occlusive disease involving all extremities in varying degrees. This was accompanied by generalized deterioration both physically and psychologically. At the time of his initial examination, there were several ulcers on the right foot and amputation of the right lower extremity had been suggested. The hands and the left foot were only moderately affected.

Following one treatment with Low Intensity Laser Therapy, symptoms diminished and physical findings improved dramatically. Needless to say, all medications except insulin were stopped. His physical status continues to improve with regular treatment (Bioflex Professional system) at a clinic located close to his home (two hours drive to Meditech).

Discussion
• It is important to categorize this situation with regard to healthcare in general and to initiate changes to alter the management of these types of clinical conditions.
• Medical supervision in this instance was clearly inadequate and the pharmacist who kept filling repeat prescriptions on demand should come under scrutiny.
• Whereas the clinicians at Meditech have not conducted tests with regard to the toxicities of the drugs in question, it has become increasingly clear to us over the years that all pharmaceuticals have side effects which may be highly undesirable.

Conclusions
• The therapeutic approach to gout requires re-evaluation.
• The initial treatment of gout should be directed to the relief of pain.
• This may include analgesics initially, however the long-term strategy should include preventative measures which treat the pathology, rather than modulating symptoms.
• A combination of pharmaceuticals may be effective on a short-term basis; the risks associated with this approach, however, must be carefully considered.
• Hyperuricemia levels may be controlled with medications initially, however the course of treatment should be monitored frequently and medications should not be considered a satisfactory long-term solution.
• Preventative measures including diet, control of diabetes, hypertension and obesity should be stressed as preventative measures.
• Low Intensity Laser Therapy in the treatment of gout is safe, effective and devoid of any complications3 and should therefore be the treatment of choice.
• Sustained good health implies the use of the minimum number of pharmaceuticals essential to the maintenance of good health.

References
1. Gutiérrez-Macías, A et al (2005) Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia
2. Singer JZ et al (1986) The allopurinol hypersensitivity syndrome: unnecessary morbidity and mortality. Arthritis Rheum
3. Soriano F et al (2006) Photobiomodulation of pain and inflammation in microcrystalline arthropathies: experimental and clinical results, Photomedicine and Laser Surgery 24(2):140-50.
4. http://www.emedicine.com/med/topic924.htm
5. Arakawa M et al (2001) Allopurinol hypersensitivity syndrome associated with systemic cytomegalovirus infection and systemic bacteremia, Internal Medicine 40(4):331-5.
6. A Kumar (1996) Allopurinol, erythema multiforme, and renal insufficiency, BMJ 312:173-174.
7. Koike M et al (2008) Viruses may trigger allopurinol hypersensitivity syndrome, NDT Plus 1(4):273-274.
8. Masaki T et al (2003) Human Herpes Virus 6 Encephalitis in Allopurinol-induced Hypersensitivity Syndrome
9. Morris I (2003) Colchicine in acute gout, BMJ 327:1275-1276.