Study dose titration

In explanatory studies, there is a tendency to compare a new treatment to placebo and to rigidly adhere to single doses of the new treatment in anticipation of maximising treatment compliance. On the other hand, pragmatic studies are more likely to compare the new treatment with the best available alternative and to use a more flexible attitude to dosing, for example, including the possibility of individual dose titration. The delivery of treatment is likely to mimic real-life usage. 

A review of 18 controlled studies in otherwise typically developing children (Moffatt et ah, 1993) demonstrated that only about 24% of children were completely dry while on medication and that 94% relapsed after medication was discontinued. In the Swedish Enuresis Trial (SWEET), 399 children aged 6-12 years with primary enuresis participated in an open, multicenter trial of DDAVP (Tullus et ah, 1999). Subjects were observed for 4 weeks and had their DDAVP dose titrated over 6 weeks (20 0 pg), followed by a 1-year long-term treatment period. A total of 245 children (61%) experienced a 50% or more reduction in the number of wet nights, with resolution of enuresis in 77 children. The greatest therapeutic effect was observed in children 6-7 years of age. There were no studies on the effectiveness of DDAVP in children with MR. 

Adverse effects. Postmarketing surveillance, in which more than 34,000 patients were studied, revealed that fluvoxamine is generally well tolerated if initial dose titration is employed (Wilde et al. 1993). By far the most common side effect reported was nausea (15.7%) other adverse effects included somnolence (6.4%), asthenia (5.1%), headache (4.8%), and dry mouth (4.8%) these events had an incidence of >1%. On reviewing the manufacturer s database, Henry (1991) found that 310 cases of overdose with fluvoxamine had been reported worldwide. The overwhelming majority recovered with no sequelae the 13 fatalities were associated with multiple substance ingestion, making the contribution of any single substance difficult to assess. 

Dose titration makes it impossible to determine, within a single study, whether there is one optimal dosage within the range studied ... 

Blood pressure and heart rate should be monitored at each visit during the dose titration phase to permit early detection of adverse effects. To minimize the risk of development of movement disorders or psychotic symptoms, psychostimulants should be used cautiously in any patient with a history of tics or psychotic symptoms, or with a family history of Tourette s syndrome or schizophrenia. Nevertheless, studies have shown that psychostimulants are effective in treating ADHD in patients with co-morbid Tourette s syndrome and that they do not exacerbate tics in the majority of such patients ( 88, 89). Furthermore, no evidence indicates that psychostimulants can lower the seizure threshold or cause seizures. 

In a double-blind study of desmopressin, 10 of 224 adult men had serum sodium concentrations below 130 mmol/1 during a 3-week, open, dose-titration period. Men aged 65 years and over were more likely to develop hyponatremia (51). 

Chew SL, Grossman AB, Besser GM, Monson JP. 67. Sustained reduction in circulating cholesterol in adult hypopituitary patients given low dose titrated growth hormone replacement therapy a two year study, din Endocrinol (Oxf) 2000 53(4) 453-9. 

Gelber DA, Good DC, Dromerick A, et al. Open-label dose-titration safety and efficacy study of tizanidine hydrochloride in the treatment of spasticity associated with chronic stroke. Stroke. 2001 32 1841-1846. 

Brevetti G, Pema S, Sabba C, et al. Propionyl-L-camitine in intermittent claudication double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995 26(6) 141 I 1416. 

In a 9-week double-blind, randomized, placebo-con-trolled study, subjects were assigned to either risperidone (n = 14, 13 men and 1 woman mean age 42 years dose titrated upwards up to 2 mg/day) or to placebo (n = 9, 6 men and 3 women mean age 39 years) (43). Adverse effects were reported in seven subjects who took risperidone, including dry mouth, tiredness, weakness, reduced sexual arousal and delayed ejaculation, and a mild dys-tonic reaction. However, five placebo-treated subjects also reported adverse effects, which might have been due to the strong tendency of these patients to become somatically preoccupied. There were no group differences in dropout rates due to adverse effects. 

Saper IR, Winner PK, Lake AE 3rd. An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache. Headache 2001 41(4) 357-68. 

Joy MS, Finn WE. Randomized, double-blind, placebo-controlled, dose-titration, Phase III study assessing the efficacy and tolerability of lanthanum carbonate a new phosphate binder for the treatment of hyperphosphatemia. Am J Kidney Dis 2003 42 96-107. 

Risperidone fulfills the atypical criterion of having a low incidence of EPS at low to moderate doses. The mean optimal dose in parallel, fixed-dose studies was 4 to 6 mg daily. At doses greater than 6 mg daily, risperidone s profile is more similar to that of an FGA. Because risperidone appears to lose its atypical profile at higher doses, the lowest possible dose should be used in treatment. This may include gradual dose titration downward if patients do not respond initially, rather than upward titration as has been the traditional approach to dosing antipsychotics. ... 

Olanzapine has a very low incidence of EPS when used within the approved dose range of 10 to 20 mg daily. However, many patients are being treated at doses above the currently recommended limit in the approved product labeling of 20 mg/day. Quetiapine is an efficacious antipsychotic with an excellent EPS profile. Although contrary to efficacy studies, doses above 500 mg are often used to achieve optimal effects, with dose titration to 800 mg/day being a... 

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