SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. The problem of fatigue in chronic liver disease
  4. Ondansetron as a potential therapy for fatigue
  5. Subjective vs. objective primary efficacy endpoints
  6. Clinical judgement and randomized controlled trials
  7. References

Profound fatigue is a clinically significant complication of chronic liver disease. A mechanism of fatigue in experimental animals and male athletes appears to be increased serotoninergic neurotransmission in the brain. Recently, attempts have been made to assess the efficacy of a serotonin antagonist, specifically the 5-HT3 receptor subtype antagonist, ondansetron, in ameliorating fatigue in patients with chronic liver disease.

However, the results of a randomized controlled trial of ondansetron for fatigue in patients with primary biliary cirrhosis did not indicate that ondansetron was either effective or ineffective. The reasons for the uncertain outcome of the randomized controlled trial are not clear. One contributing factor may have been the use of subjective indices of fatigue as primary efficacy endpoints. There is a need to develop objective quantitative primary efficacy endpoints for use in trials of therapy for fatigue.

Another contributing factor may relate to the conduct of a randomized controlled trial not invariably being the optimal approach to resolve a specific clinical issue, particularly when the application of statistical methods yields equivocal findings. When the results of a randomized controlled trial are indecisive, findings based on clinical judgement, medicine's most important asset, should be carefully evaluated.


The problem of fatigue in chronic liver disease

  1. Top of page
  2. Summary
  3. The problem of fatigue in chronic liver disease
  4. Ondansetron as a potential therapy for fatigue
  5. Subjective vs. objective primary efficacy endpoints
  6. Clinical judgement and randomized controlled trials
  7. References

Clinically significant fatigue may occur in patients with certain chronic liver diseases, such as primary biliary cirrhosis (PBC) and chronic hepatitis C. This symptom tends to be particularly apparent when such patients are referred to hepatologists.1 In PBC, fatigue has been reported to be the most common and disabling symptom.2, 3 It is often difficult to assess whether fatigue in a patient with chronic liver disease is attributable to the patient's knowledge of the nature of the disease, the presence of a factor that causes the disease, the chronic disease process or the presence of chronic liver disease.1, 4

Ondansetron as a potential therapy for fatigue

  1. Top of page
  2. Summary
  3. The problem of fatigue in chronic liver disease
  4. Ondansetron as a potential therapy for fatigue
  5. Subjective vs. objective primary efficacy endpoints
  6. Clinical judgement and randomized controlled trials
  7. References

Although several hypotheses of the pathogenesis of fatigue in patients with chronic liver disease have been considered, the validity of none has been confirmed.1 However, the hypothesis that increased central serotoninergic neurotransmission may be a mechanism of fatigue has received the most attention. Two studies in particular have implicated the serotonin system in the mediation of fatigue. In rats, it was reported that fatigue during prolonged exercise (on a treadmill) was associated with elevated brain levels of 5-HT, animals treated with a 5-HT antagonist (LY53857) were able to exercise longer, and administration of a 5-HT agonist (quipazine dimaleate) decreased the time to exhaustion.5 Furthermore, in a placebo-controlled study, paroxetine, a serotonin reuptake inhibitor, which effectively acts as a serotonin agonist, has been shown to decrease exercise tolerance in male athletes.6 These findings led, in 1995, to the suggestion that increased central serotoninergic tone may contribute to the mediation of fatigue complicating chronic liver disease, although the rather tenuous nature of the extrapolation was recognized. Nevertheless, this hypothesis appeared to provide a rationale for a randomized controlled trial (RTC) of a serotonin antagonist, such as the serotonin 5-HT3 receptor subtype antagonist, ondansetron, in patients with fatigue and chronic liver disease.7

Subsequently, the basis for this hypothesis was discussed further,8, 9 and a case study was published, in which successive long-term courses of treatment with orally administered ondansetron consistently appeared to ameliorate profound fatigue in a patient with chronic hepatitis C.10 Indeed, when taking the drug the patient was able to do more piece work and, hence, earn more money. In this context, the conduct of a RCT of ondansetron for fatigue in patients with PBC by Theal et al. is potentially important;11 their study is the first published RCT of this particular drug as a treatment for fatigue in patients with chronic liver disease.

The study of Theal et al. had a multicentre, randomized, double-blind, placebo-controlled, cross-over design. Primary efficacy endpoints were data obtained by applying a fatigue severity score12 and a fatigue impact scale.13 The number of patients studied, who did not drop out, was substantial, and the report of the study indicates that it was competently conducted. An adverse effect on the blinding of the study, due to the occurrence of a well-recognized side effect of ondansetron, constipation, probably could not have been avoided. Unfortunately, conventional analysis as well as sophisticated statistical analyses of the data obtained, did not enable any definitive conclusions to be drawn. In other words, it was not possible to infer that ondansetron was either efficacious or non-efficacious in ameliorating fatigue in patients with PBC. Potential explanations for the indecisive outcome of this RCT may relate to the nature of the primary efficacy endpoints that were used, which were subjective, and the possibly related issue of whether the conduct of a RCT to attempt to resolve the particular clinical issue that was addressed was entirely appropriate.

Subjective vs. objective primary efficacy endpoints

  1. Top of page
  2. Summary
  3. The problem of fatigue in chronic liver disease
  4. Ondansetron as a potential therapy for fatigue
  5. Subjective vs. objective primary efficacy endpoints
  6. Clinical judgement and randomized controlled trials
  7. References

Fatigue associated with liver disease is an inherently subjective perception and, consequently, cannot be measured. The discipline of clinical science requires that objective quantitative primary efficacy endpoints be incorporated into the design of trials of the efficacy of new drugs in ameliorating specific disease-related phenomena whenever possible. Unfortunately, the various scores of fatigue that have been generated, including fatigue severity scores and fatigue impact scales,12–16 do not seem to be sufficiently objective to meet fully the rigorous requirements of clinical science. Application of such scores generates numbers that lack units and tend to be arbitrary.

Analogous problems have arisen in the design of trials of new therapies for pruritus in patients with chronic liver disease. Pruritus is also an inherently subjective perception that cannot be measured. In many studies of pruritus in patients with liver disease visual analogue scales have been applied to generate scores of the severity of pruritus (i.e. subjectively derived numerical data). Problems inherent in applying such scales to assess the efficacy of new treatments have been critically reviewed by McCormack et al.17 and some of these problems have recently been re-emphasized in relation to the pruritus of cholestasis.18 In contrast to pruritus, scratching activity, which can be defined as the behavioural consequence of pruritus, can be objectively quantitated. To obtain a more objective primary efficacy endpoint in trials of new therapies for pruritus, devices, in which piezofilm technology has been applied to quantitate scratching activity directly, independent of arm or hand movements, have been developed.19, 20 Such devices have been validated19, 20 and have been successfully applied in RCTs, which have demonstrated the efficacy of opiate antagonists in reducing scratching activity in patients with chronic liver disease, particularly chronic cholestatic disease.21–24

So far, there is no consensus regarding which measurements might constitute a satisfactory objective quantitative primary efficacy endpoint in trials of therapies for fatigue. One possibility is to measure exercise tolerance.25 However, exercise tolerance is primarily a measurement of fatigue of peripheral origin; such a measurement may be inappropriate as an index of fatigue in a disease, such as PBC, in which fatigue may have a central origin.26 Other objective indices of fatigue may include measurements of grip strength,27 and the force of muscle contractions.26 However, the appropriateness of none of these measurements, as an objective quantitative primary efficacy endpoint in trials of therapies for fatigue, has been established.

Clinical judgement and randomized controlled trials

  1. Top of page
  2. Summary
  3. The problem of fatigue in chronic liver disease
  4. Ondansetron as a potential therapy for fatigue
  5. Subjective vs. objective primary efficacy endpoints
  6. Clinical judgement and randomized controlled trials
  7. References

With respect to ondansetron and fatigue complicating liver disease, it may be appropriate to point out that RCTs, although widely considered to be the gold standard in establishing the efficacy of a specific drug for the treatment of a particular disease or symptom, do not necessarily always represent the final court of appeal when addressing specific clinical issues.28 Le Fanu has elaborated on this line of reasoning in a comprehensive and extensively referenced review of how the status of clinical science has evolved in recent decades.29 The following quotes, which may not be universally true, but may well be applicable when certain specific clinical problems are addressed, are taken from his provocative review. A ‘feature of scientific progressivism’ is ‘the belief that it can explain everything. This intellectual hubris of not recognising what is not known opens the door to false explanations’. ‘Medical science now recognises only one source of knowledge, that which has ‘‘been proven’’ by statistics, and this’ can be ‘a potent source of error. There are many ways of knowing and among the most powerful is the tacit knowledge that comes from experience and is best described as “judgement”’.30, 31 This ‘form of knowledge’ is not necessarily ‘less reliable and inferior to that which can be objectively and explicitly demonstrated with statistical techniques and clinical trials’. ‘Statistically derived knowledge’ may be ‘unreliable’, and may be used to promote ‘the patently absurd as proven fact. Further, clinical trials cannot answer the sort of complex questions that frequently crop up in medical practice’. ‘Perversely,...scientific progressivism has undermined medicine's most important asset-knowledge based on practical experience, allied with ‘‘a reasoning faculty’’ that can distinguish the true from the false’. ‘Sometimes – perhaps even often – the ‘‘clinical wisdom’’ of doctors assessing the efficacy of treatment based on their own personal experience may, after all, be a better guide to medical practice than ‘‘the objectivity’’ of the clinical trial’.29

Thus, in some clinical circumstances, rigorous application of sound clinical judgement may be an alternative option to undertaking a RCT in assessing the efficacy of a new drug. Clinical judgement can be defined as ‘the ability to make considered decisions or come to sensible conclusions’ (New Oxford Dictionary of English) in a clinical context. In addressing the problem of ameliorating fatigue, clearly the subjective impression of the patient cannot be ignored, but it must be given due weight. Other factors may contribute to the overall clinical judgement, such as careful questioning regarding the patient's ability to undertake specific activities and the experience and competence of the evaluating clinician. To avoid bias and control for a placebo effect, the effect of a new treatment may be compared to that of a placebo in a blinded fashion outside the context of a RCT. In practice, it is desirable to evaluate each patient as an individual.

Currently, there is a lack of an objective quantitative primary efficacy endpoint for incorporation into the design of trials of new therapies for fatigue. The discipline of clinical science requires that, if possible, this type of endpoint should be used in such trials. Until a more acceptable endpoint becomes available, it may, perhaps, be prudent, in accordance with Le Fanu's thesis,29 to take into account data obtained by conscientiously applying medicine's most important asset, sound clinical judgement, in addition to those obtained from RCTs, in assessing the efficacy of new therapies for fatigue complicating chronic liver disease.

References

  1. Top of page
  2. Summary
  3. The problem of fatigue in chronic liver disease
  4. Ondansetron as a potential therapy for fatigue
  5. Subjective vs. objective primary efficacy endpoints
  6. Clinical judgement and randomized controlled trials
  7. References
  • 1
    Jones EA. Fatigue complicating chronic liver disease. Metab Brain Dis 2004; 19: 4219.
  • 2
    Witt-Sullivan H, Heathcote J, Cauch K, et al. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology 1990; 12: 98105.
  • 3
    Cauch-Dudek K, Abbey S, Stewart DE, Heathcote EJ. Fatigue in primary biliary cirrhosis. Gut 1998; 43: 70510.
  • 4
    Wessely S, Pariante C. Fatigue, depression and chronic hepatitis C. Psychol Med 2002; 32: 110.
  • 5
    Bailey SP, Davis JM, Ahlborn EN. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J Appl Physiol 1993; 74: 300612.
  • 6
    Wilson WM, Maughan RJ. Evidence for a possible role of 5-hydroxy-tryptamine in the genesis of fatigue in man: administration of paroxetine, a 5-HT re-uptake inhibitor, reduces the capacity to perform prolonged exercise. Exp Physiol 1992; 77: 9214.
  • 7
    Jones EA. Fatigue associated with chronic liver disease: a riddle wrapped in a mystery inside an enigma. Hepatology 1995; 22: 16068.
  • 8
    Jones EA, Yurdaydin C. Is fatigue associated with cholestasis mediated by altered central neurotransmission? Hepatology 1997; 25: 4924.
  • 9
    Jones EA. Altered central serotoninergic neurotransmission: A potential mechanism for profound fatigue complicating chronic hepatitis C. Med Hypotheses 2001; 57: 1334.
  • 10
    Jones EA. Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. Lancet 1999; 354: 397.
  • 11
    Theal JJ, Toosi MN, Girlan L, et al. A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue. Hepatology 2005; 41: 130512.
  • 12
    Schwartz JE, Jandorf L, Krupp LB. The measurement of fatigue: a new instrument. J Psychosom Res 1993; 37: 75362.
  • 13
    Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the Fatigue Impact Scale. Clin Infect Dis 1994; 18 (Suppl): S7983.
  • 14
    Elkins LE, Krupp LB, Scherl W. The measurement of fatigue and contributing neuropsychiatric factors. Semin Clin Neuropsychol 2000; 5: 5861.
  • 15
    Kleinman L, Zodat MW, Hakim Z, Aledort J, Barker C, Chank D. Psychometric evaluation of the fatigue severity scale for use in chronic hepatitis C. Qual Life Res 2000; 9: 499508.
  • 16
    Prince MI, James OF, Holland NP, Jones DE. Validation of a fatigue impact score in primary biliary cirrhosis: Towards a standard for clinical and trial use. J Hepatol 2000; 32: 36873.
  • 17
    McCormack HM, de L'Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical review. Psychol Med 1988; 18: 100719.
  • 18
    Jones EA. Trials of opiate antagonists for the pruritus of cholestasis: primary efficacy endpoints and opioid withdrawal-like reactions. J Hepatol 2002; 37: 8645.
  • 19
    Talbot TL, Schmitt JM, Bergasa NV, Jones EA, Walker EC. Application of piezofilm technology for the quantitative assessment of pruritus. Biomed Instrum Technol 1991; 25: 4003.
  • 20
    Molenaar HAJ, Oosting J, Jones EA. Improved device for measuring scratching activity in patients with pruritus. Med Biol Eng Comput 1998; 36: 2204.
  • 21
    Bergasa NV, Talbot TL, Alling DW, et al. A controlled trial of naloxone infusions for the pruritus of cholestasis. Gastroenterology 1992; 102: 5449.
  • 22
    Bergasa NV, Alling DW, Talbot TL, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind randomized controlled trial. Ann Intern Med 1995; 123: 1617.
  • 23
    Bergasa NV, Schmitt JM, Talbot TL, et al. Open label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998; 27: 67984.
  • 24
    Bergasa NV, Alling DW, Talbot TL, Wells MC, Jones EA. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol 1999; 41: 4314.
  • 25
    Bruce RA. Exercise testing of patients with coronary disease. Principles and normal standards for evaluation. Ann Clin Res 1971; 3: 32332.
  • 26
    Jalan R, Gibson H, Lombard MG. Patients with PBC have central but not peripheral fatigue. Gut 1996; 39 (Suppl. 1): A30.
  • 27
    Goldblatt J, James OF, Jones DE. Grip strength and subjective fatigue in patients with primary biliary cirrhosis. J Am Med Assoc 2001; 285: 21967.
  • 28
    Feinstein AR. An additional basic science for clinical medicine: II. The limitations of randomized trials. Ann Intern Med 1983; 99: 54450.
  • 29
    Le Fanu J. Twelve defining moments. Looking to the future. In: The Rise and Fall of Modern Medicine. London: Little, Brown and Company, 1999: 57 and 406–7.
  • 30
    Goldman GM. The tacit dimension of clinical judgement. Yale J Biol Med 1990; 63: 4761.
  • 31
    Tanenbaum SJ. What physicians know. N Engl J Med 1993; 329: 126871.