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Clomipramine Vs Desipramine Vs Placebo in the Treatment of Diabetic Neuropathy Symptoms

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Clomipramine Vs Desipramine Vs Placebo in the Treatment of Diabetic Neuropathy Symptoms Br. J. clin. Pharmac. (1990), 30, 683-691 Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind cross-over study S. H. SINDRUP', L. F. GRAM', TINA SKJOLD2, ELLEN GRODUM3, K. BR0SEN' & H. BECK-NIELSEN3 Departments of 'Clinical Pharmacology, Odense University, 2Internal Medicine, Fredericia Hospital and 3Endocrinology, Odense University Hospital, Odense, Denmark 1 The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day-1 and 200 mg desipramine day-1 whereas poor metabolisers were treated with 50 mg day- ofboth drugs. Nineteen patients completed the study. 2 Plasma concentration of clomipramine plus desmethylclomipramine was 70-510 nm in extensive metabolisers, vs 590 and 750 nm in two poor metabolisers. Desipramine levels were 130-910 nM, vs 860 and 880 nM. 3 Both clomipramine and desipramine significantly reduced the symptoms of neuro- pathy as measured by observer- and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethyl- clomipramine < 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4 Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5 Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy. Keywords clomipramine desipramine diabetic neuropathy Introduction Tricyclic antidepressants are widely used in the to placebo. For both imipramine (Kvinesdal et treatment of the symptoms of peripheral dia- al., 1984; Sindrup et al., 1989, 1990a,b) and betic neuropathy. Imipramine (Kvinesdal et al., amitriptyline (Max et al., 1987), a correlation 1984; Sindrup et al., 1989, 1990a), amitriptyline between plasma drug concentration and effect (Max et al., 1987) and nortriptyline (Gomez- has been established. Perez et-al., 1985) have in randomised, double- Tricyclic antidepressants are known to block blind, cross-over trials been shown to be superior a1-adrenergic, H,-histaminergic and muscarinic Correspondence: Dr S0ren H. Sindrup, Department of Clinical Pharmacology, Odense University, J. B. Winsl0ws Vej 19, DK-5000 Odense C, Denmark 683 684 S. H. Sindrup et al. cholinergic receptors, and presynaptic re- tuted whenever possible. Drug doses were ad- uptake of 5-hydroxytryptamine (5-HT) and justed according to the sparteine phenotype as noradrenaline (Gram, 1983). Due to the existence the metabolism of clomipramine (Balant-Gorgia of an endogenous pain suppressing system et al., 1986) and desipramine (Br0sen et al., (Fields & Basbaum, 1984), dependent on opiates, 1986) to some extent depend on the sparteine 5-HT and noradrenaline, interest has focused oxygenase. In extensive metabolisers (EM) of on the monoamine reuptake inhibition as the sparteine (metabolic ratio (MR) < 20) (Br0sen mechanism of action of these drugs in this et al., 19852, drug doses were clomipramine condition. In a recent study (Sindrup et al., 75 mg day- and desipramine 200 mg day-1, in 1990a) we have shown that the selective 5-HT poor metabolisers (PM) (MR > 20), it was 50 mg reuptake inhibitor paroxetine is effective in the day-1 for both drugs. Clomipramine hydro- treatment of diabetic neuropathy symptoms. chloride 25 mg (Anafranilg, CIBA-GEIGY), By appropriate dosing according to plasma drug desipramine hydrochloride 25 mg (Pertofran®', level monitoring, paroxetine may become as CIBA-GEIGY) and placebo tablets were of efficacious as imipramine (Sindrup et al., 1990a). identical size and colour. EM were given eight However, this does not exclude that interaction tablets (five additional placebo tablets in the with noradrenergic receptor systems could be clomipramine period) and PM were given two of importance and experimental studies have tablets in each of the three double-blind treat- also indicated that certain antihistamines possess ment periods as a single dose at 20.00 h. One analgesic properties (Bjerring, 1990). Further- patient (no 21, Table 1) was erroneously pheno- more, it has been claimed that tricyclic anti- typed as PM due to inhibition of the sparteine depressants interact with rat brain opiate oxygenase by concomitant intake of dextro- receptors at concentrations reached in vivo propoxyphene (Sanz et al., 1989) before in- (Biegon & Samuel, 1979, 1980), although there clusion. Accordingly, this patient was treated is some controversy on this assumption (Hall & with the PM doses of clomipramine and desipra- Ogren, 1981). mine during the trial. Phenotyping was repeated Obviously, the mechanism of action of tricyclic after the trial and the patient was now classified antidepressants in the treatment of diabetic as EM. The treatment periods were separated by neuropathy symptoms is not finally settled. at least 1 week for washout in EM, while the Some of the classical TCA differ markedly in washout periods were extended to at least receptor profile, e.g. clomipramine acts pre- 3 we'eks in PM, due to the very long elimination dominantly as a 5-HT reuptake inhibitor (Hyttel, half-life of desipramine in this phenotype 1984), but its metabolite desmethylclomipramine (Br0sen etal., 1986). On the 13th and 14th day of inhibits the reuptake of both 5-HT and nor- each treatment period, blood for drug level adrenaline. In contrast, desipramine is a rather measurements was collected at 08.00-09.00 h. selective noradrenaline reuptake inhibitor Clomipramine, desmethylclomipramine and without metabolites with effect on 5-HT reuptake desipramine were assayed by quantitative thin (Gram, 1983). Clomipramine and to a less de- layer chromatography (Gram et al., 1983). The gree desipramine also block al-adrenergic, lower level of detection was 10 nm and the inter- H1-histaminergic and muscarinic cholinergic assay coefficient of variation was 7-10%. All receptors (Gram, 1983). To examine the possible assays were run in duplicate. significance of these receptor differences we performed a randomised, double-blind, cross- Patients over trial with clomipramine vs desipramine vs placebo. Patients were recruited from two diabetic out- patient clinics and from general practitioners. They all had neurological signs of peripheral neuropathy and were troubled by several of Methods the following symptoms: pain, paresthesia, dysesthesia, nightly exacerbation and sleep Study design and medication disturbances. The distribution of symptoms were typical for peripheral neuropathy. None The study period comprised one week for base- had renal or cardiac dysfunction, a diagnosis of line observations followed by a double-blind pernicious anaemia, reduced serum levels of treatment for 2 + 2 + 2 weeks with clomipra- vitamin B12 or folic acid, or untreated hypo- mine, desipramine and placebo in random thyroidism. order. The randomisation was carried out in Twenty-six patients were included. Six patients blocks of six patients and drop-outs were substi- withdrew due to side effects; three during Clomipramine and desipramine in diabetic neuropathy 685 - o 0 + ON (A AtW (A W -n"so ooou O IV . cn "a 0. '- (D Pz 5 0_. (ID CD _F 0 C4 It 0 = CZ 3 CD Pz D 0 . 0 A. .< 0. P0 _+ 0 F) crCD - ~0~ 0 U0~-J0Aoo000 000oo oo00-.o 0 I CD " " 0 _. 0 - Ut 0 N t- 4" 0 00UtU b 0 o _. 0 Xt t, W-P> > .AC)" Aw (A --w .(=" ( t z S: CD 2 (A &- Co-+ 0 am- r 0:. 0 0m CD0r OrPQ(rQ co t-0s - Y ,^ _ _ aP Z Q CD CDP Z." CDu 14 l I'd 00 'IO 00 'IO 00 Ot Ot 2 - 00 Ot , 00 . - - X t:. z- oo oo t:l t. -0 t. 00 tz. z t. P t. P , z zzt.z z zzz, z z R. 0 ++ ++++I++++++++++ t-. cu M ZI:0 0 0-1) I+++++++I I+I I+I I++ 2-. C r^ (t. 0-I 0o0 + + + +++I +++I ++++I ++ 0~ 686 S. H. Sindrup et al. clomipramine (nausea, dizziness, tiredness, con- port symptoms that started or worsened during fusion) in the first active treatment period and each treatment period. three during desipramine (nausea, tiredness, Statistical analyses were carried out by the dizziness) in the first (two patients) or second Mann-Whitney test, the Kruskal-Wallis test, (one patient) active treatment period. One The Friedman test, the Page test, the Wilcoxon's patient dropped out due to lack of pain relief test for pair differences, and Spearman rank after 1 day on clomipramine. Nineteen patients correlation using the MEDSTAT program thus completed the study. Clinical data on these package version 2.1 (Wulff & Schlichting, 1988). patients are given in Table 1. Three patients (nos An extension of the Friedman test was used for 5, 10, 23) showed only minor neurological comparison of treatments against each other and deficits, in two of 'iese (nos 10 and 23) the against placebo (Siegel & Castellan, 1988). diagnosis of periph.:ral neuropathy was con- The study was approved by the regional ethics firmed by nerve conduction and EMG studies. committee, and patients consented to partici- In one patient (no 18) ankle/arm systolic blood pate on the basis of verbal and written infor- pressure index was below 0.9 bilaterally and mation. arterial insufficiency could thus partly be re- sponsible for the symptoms. Sixteen patients were insulin treated, while three (nos 9, 23, 24) were treated with glibenclamide and/or Results metformin. Table 2 lists treatment sequences, sparteine Effect recording and evaluation phenotypes, plasma drug concentrations, and the scores on the observer and self rating neuro- At the end of each treatment period, the neuro- pathy scale during placebo, clomipramine and pathy symptoms were assessed by a physician desipramine.
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