Double Blind Comparison of Lithium and Verapamil in Cluster Headache Prophylaxis
G. Bussone,* M. Leone,* C. Peccarisi,* G. Micieli,** F. Granella,*** M. Magri,**** G.C. Manzoni,*** and G. Nappi** *Headache
Centre, C. Besta Neurological Institute of Milan, Italy. of Neurology, University of Pavia, Italy. ***Clinic of Neurology, University of Parma, Italy. ****Medical Department, Knoll Spa of Milan, Italy. **Clinic
Reprint requests to: Dr. Gennaro Bussone, Istituto Neurologico "C. Besta," Via Celoria, 11, 20133 Milano (Italy). Accepted for Publication: May 6, 1990. SYNOPSIS
Chronic Cluster Headache (CCH) treatment is troublesome; since there are no pain-free periods, it must be continuous. The most effective CCH prophylactic drug today is lithium carbonate but long-term use of this drug is limited by the possibility of side effects. Recently, calcium antagonists have been successfully employed to prevent migraine, and preliminary studies also indicate that verapamil in particular is an efficacious treatment for CCH. We have conducted a multicenter trial employing a double-dummy, double blind, cross-over protocol, comparing verapamil with the established efficacy of lithium carbonate, in preventing CCH attacks. Both lithium carbonate and verapamil were effective in preventing CCH but verapamil caused fewer side effects and had a shorter latency period. We did not observe any correlation between plasma levels of the two drugs and their clinical efficacy. Both the drugs tested here may exert their effect by restoring a normal inhibitory tone to the pain modulating pathways from the trigemino-vascular system, a circuit putatively implicated in CCH. (Headache 30:411-417, 1990) INTRODUCTION
Therapy in cluster headache (CH) is particularly important in view of the rapidity of onset and the violence of the pain attacks, and the difficulty in controlling them with analgesics. Chronic cluster headache (CCH) is even more troublesome because there are no pain-free periods1 and treatment must be continuous. An enlargement of the therapeutic armamentarium for controlling this form of the illness would be highly desirable. The most effective CCH prophylactic today is lithium carbonate2 but long-term use of this drug is limited by the likelihood of side effects.3 Recently, calcium antagonists have been successfully employed to prevent migraine4,5,6,7,8,9 and preliminary studies also indicate that verapamil in particular is an efficacious treatment for CCH6; such studies in CCH have been of the open type, however, and there is a clear requirement for a double blind trial to verify or refute these initial findings. With this aim we conducted a multicentre double-blind trial comparing verapamil with the established efficacy of lithium carbonate. PATIENTS AND METHODS
Thirty subjects attending the Headache Centres at Milan, Pavia and Parma, and diagnosed as afflicted with chronic cluster headache according to International Headache Society (IHS) criteria,1 were included in the study. Subjects, all of whom gave their informed consent, were of both sexes and aged between 20 and 60 (Table 1). Specifically excluded were patients with cardiovascular, pulmonary, renal or liver conditions; so too were pregnant women and those taking oral contraceptives and prophylactic drugs for CH. Table 1 Clinical Aspects N 30 Age (yrs) 43 ± 11 Sex Male 27 Duration of Illness (yrs.) 9±5 Primary Chronic 18 Cluster Headache Secondary Chronic 12 Cluster Headache
Min 20 - Max 59 Female 3 Min 2 - Max 19
The trial was conducted employing a double-dummy, double-blind crossover protocol and lasted a total of 23 weeks (Figure 1). Each subject was administered wash-out/placebo for the first 2 weeks. Verapamil at 360 mg/day or lithium carbonate at 900 mg/day in 3 doses daily was given by randomized assignment starting from the 1st day of the 3rd week for 8 weeks. At the end of the 10th week all patients began a second wash-out/placebo phase, followed, commencing the 1st day of the 13th week, by the second 8-week treatment period. In this second period, patients who had received verapamil in the first period received lithium, and vice-versa. The final wash-out/placebo period, lasting 3 weeks, began after the completion of the 20th week. On the 1st,
14th and 56th days of both treatment periods, and at the end of the 23 weeks of the trial, patients were given electrocardiograms (ECG) and blood and urine tests. Lithium and verapamil levels in blood were determined on the 14th and 56th day of each treatment period. Patients were allowed access to NSAIDs as required throughout the entire trial period. Analgesics consumption and the intensity, frequency and duration of attacks were recorded daily on a diary card. Statistical evaluation was performed by cross-over multi-variant analysis of variance of the headache index (HI) and analgesic consumption (AC). Correlation between serum drug levels and clinical efficacy was also analysed. RESULTS
Only 24 of the 30 patients completed the study; six dropped out because of poor compliance during the first placebo wash-out. Clinical Efficacy: Both lithium and verapamil produced significant improvements in HI and AC (p < 0.01 ) (Figures 2 and 3). Over 50% of patients receiving verapamil experienced a reduction in HI during the 1st week, while lithium produced an HI improvement only in 37% of patients in the 1st week (Table 2). AC reduction was 58% in both treatment groups over the same period. Side Effects: 12% of patients receiving verapamil and 29% of patients receiving lithium reported side effects but these were never severe enough to warrant abandoning the treatment (Table 3). No significant changes in ECGs, blood pressure or blood and urine test results were observed over the trial period. Verapamil and Lithium Serum Levels: In 15 verapamil and 18 lithium patients it was possible to measure drug plasma levels at the 2nd and the 8th week of treatment (Figure 1). Mean verapamil level in blood on the 14th day of treatment was 83.5 ± 47 ng/I; on the 56th day it was 91.6 ± 68.8 ng/1. The corresponding values for lithium were 0.413 ± 0.1 meq/1 and 0.465 ± 0.1 meq/1 respectively; with neither drug was there a significant difference between the initial and final values. Dose/Effect Correlation: A numerical factor named delta expresses the differences in HI and drug plasma levels between the 2nd and the 8th week during each treatment. Relationships between delta HI and the corresponding deltas for drug plasma levels were investigated. Verapamil: no significant correlation was observed between verapamil and HI deltas (r = -0.05; P = ns; Figure 4). Lithium carbonate: a significant correlation was found between lithium and HI deltas (r = 0.74; P < 0.05; Figure 5, see discussion). DISCUSSION
In this study both lithium carbonate and verapamil were efficacious in preventing chronic cluster headache but verapamil caused fewer side effects (Table 3) and had a shorter latency period (Table 2). It is noteworthy that plasma levels of both drugs did not vary significantly from the 2nd to the 8th week of treatment, so that the significant correlation between
increase in plasma lithium (average 0.06 meq/1) and HI reduction is probably explained by the prolonged latency period for lithium effectiveness, a latency illustrated by the fact that by the end of the 1st week 50% of verapamil subjects showed clinical improvement but only 37% of lithium subjects did so. The mechanisms of action of neither lithium nor verapamil, in CCH prophylaxis, are known. Neither is the pathogenesis of CH understood.10,11 A "peripheral" source of pain in CH has not been proved and the idea of a vascular genesis in particular is now subject to considerable doubt.12,13,14,15,16,17 It seems ever more likely that the central nervous system (CNS) is involved in CH pathogenesis18 and that the vascular manifestations are merely epiphenomena.19 That lithium is a CH prophylactic is consistent with the central theory. The drug is known to interfere with CNS neurotransmitter metabolism,20,21 affecting particularly the serotoninergic system. Its long-term administration causes modifications to the pattern of serotonin release in the rat brain so that, for example, spontaneous release is reduced in the hippocampus and increased in the hypothalamus.22 Lithium also promotes tryptophan uptake in various cerebral areas, but not the cortex.23 Again, lithium is able to modulate the serotoninergic response to various stimuli, interfering with serotonin receptors or with their associated transduction systems.22 Lithium does not seem to modify noradrenaline release significantly.22 It is known that lithium is able to interfere with the physiological architecture of sleep,24 a fact of particular relevance when it is recalled that CH attacks tend to occur during sleep. Lithium has also been shown to reduce the asymmetric manifestations, of probable central origin, which occur in CH, normalising the response to tyramine eye-drops25 and restoring the asymmetries of the evoked potentials which are altered in that illness.26 The suggestion that lithium's therapeutic action in CH depends on its interference with certain CNS neuronal pathways is further supported by its efficacy
Table 2 Headache Index Improvement after Weeks Needed to Achieve the First Seven the Improvement of 50% Days of Treatment of the Treatment Patients N % Verapamil Lithium
12 9
50% 37%
1 2
in endogenous depression, which is of known central origin.27 It has been proposed that lithium acts here by restoring normal serotoninergic tone in the CNS.28 Verapamil too appears efficacious in the treatment of endogenous depression,29 as well as reducing other symptoms of central origin such as anxiety and disturbed behaviour.30 It is a phenylalkylamine derivative which exerts its calcium antagonist effect by interfering with the slow calcium channels (membrane structures called voltage operated channels) and thus modulates the calcium flux across cell membranes.31 Until recently it was thought that calcium antagonists only Table 3 Side Effects Verapamil
Lithium
Total Occurrence Constipation or Gastrointestinal Complaints Postural Hypotension, Cardiovascular Complaints Skin Rash Behavioural Changes Tremor Increased Diuresis Others
N 3
% 12%
N 7
% 29%
-
-
3
43%
2
67%
1
14%
-
-
-
-
2 1
67% 33%
3 1 2 2
43% 14% 29% 29%
affected cardiac and smooth muscle cells, so that a vascular mechanism of action for these drugs was proposed to account for their preventing headache.32 Other observations indicate, however, that calcium antagonists like verapamil act via a mechanism which
is not predominantly vascular. Variations in regional cerebral blood flow (rCBF) and cerebrovascular response to various stimuli were monitored in groups of CH and migraine patients while undergoing treatment with calcium antagonists, with the aim of observing correlations between cerebral hemodynamics and drug efficacy.32,33 Results showed that verapamil was more efficacious than other calcium antagonists in treating CH, but induced minimal changes in cerebral circulation which, in any event, were less than those produced by other calcium antagonist drugs. This poor correlation between vascular effects and clinical efficacy suggests that the cerebral vascular bed may not be the main site of action of verapamil in CH prophylaxis. Other studies indicate that verapamil is able to modulate central neuronal activity by several mechanisms: it may influence muscarinic,34,35 serotoninergic,36,37 dopaminergic and noradrenergic receptors.38,39,40 Verapamil seems to affect hypothalamic and noradrenergic functions in animals in vivo.41 Other systemically administered calcium antagonists also seem able to modify hypothalamic/ noradrenergic activity; the action appears mediated by rapid activation of specific hypothalamic enzymes.42 Of all the cerebral transmitter systems, it is the opiate system which is particularly sensitive to verapamil. When the drug is administered in high doses it is able to modify the analgesic effect of morphine. When administered systemically at low doses it modulates the inhibitory action that hypothalamic peptides exert on morphine-induced analgesia.43 In effect, it appears able to restore correct function of the analgesic system in the presence of an excess of these hypothalamic peptides-an action the drug exerts after a short latency period.43 The more rapid action of verapamil in CCH prophylaxis, noted also in the treatment of depression,29 compared with lithium, is therefore possibly explained by the different mechanisms of action of these drugs in the CNS. It may be that lithium acts mainly by restoring serotonergic tone,44 while verapamil's effect could be due to a neuromodulatory action on the opiate system.43 The role of the serotonergic and opiate systems on pain pathways is well understood.45,48,47 Both the drugs tested here might, therefore, exert their effect by restoring a normal inhibitory tone acting on sensory pain pathways. Acknowledgement: We wish to thank F. Macciardi MD (Psychiatry Institute, University of Milan) for statistical evaluation. REFERENCES
1.
Headache Classification Committee of the International Headache Society: Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain. Cephalalgia 8, Suppl. 7, 1988.
2.
Boiardi A, Bussone G, Merati B, Tansini E, Boeri R: Course of chronic cluster headache. Ital J Neurol Sci 1:75-78, 1983.
3.
Ekbom K: Treatment of cluster headache: episodic and chronic. Ed. Blau JN. Migraine: Clinical, therapeutic, conceptual and research aspects. London, Chapman and Hall, pp 223-237, 1987.
4.
Bussone G, Baldini S, D'Andrea G, Cananzi A, Frediani F, Caresia L, Ferro Millone F, Bioardi A: Nimodipine versus Flunarizine in common migraine: a controlled pilot trial. Headache 27:76-79, 1986.
5.
Bussone G, Leone M, Bioardi A: II Verapamil nella terapia della cefalea. Ed. Richichi I and Nappi G. Cefalee di interesse cardiovascolare. Confinia Cephalalgica, Roma, Cluster Press, pp 171-177, 1988.
6.
Jonsdottir M, Meyer JS, Rogers LR: Efficacy side effects and tollerance compared during headache treatment with three different calcium blockers. Headache 27:364-369, 1987.
7.
Meyer JS, Dowell R, Mathew N, Hardenberg J: Clinical and hemodynamic effects during treatment of vascular headaches with Verapamil. Headache 24:313-321, 1984.
8.
Olesen J: Role of calcium entry blockers in the prophylaxis of migraine. Eur Neurol 25:72-79, 1986.
9.
Micieli G, Trucco M, Agostinis C, Mancuso A, Papalia F, Sinforiani E: Nimodipine versus pizotifen in common migraine: results of a double blind cross-over trial. Cephalalgia 5, suppl 3:532-533, 1985.
10.
Nappi G, Savoldi F: Le cefalee. Sistema diagnostico e criteri di classificazione. Milano, Workshop Italiana Editrice, 1980.
11.
Kudrow L: Cluster headache: mechanisms and management. Oxford, University Press, 1980.
12.
Norris JW, Hachinski VC, Cooper PW: Cerebral blood flow changes in cluster headache. Acta Neurol Scand 54:371-374, 1976.
13.
Henry PY, Vernhiet J, Orgogozo JM, Caille JM: Cerebral blood flow in migraine and cluster headache. Res Clin Stud Headache 6:81-88, 1978.
14.
Sakai F, Meyer JS: Regional cerebral hemodynamics during migraine and cluster headache measured by 133 Xe inhalation method. Headache 18:122-132, 1978.
15.
Nelson RF, DuBoulay GH, Marshall J, Ross Russell RW, Symon L, Zilka K: Cerebral blood flow studies in patients with cluster headache. Headache 20:184-189, 1980.
16.
Aebelholt-Krabble A, Henrinksen L, Olesen J: Tomographic determination of cerebral blood flow during attacks of cluster headache. Cephalalgia 4:17-23, 1984.
17.
Russell D, Lindegaard KF: Cluster headache: doppler examination of the extracranial arteries. Cephalalgia 5, suppl 3:276-277, 1985.
18.
Bussone G, Leone M: Cluster headache: a hypothalamic involvement. Functional Neurology 1989 (In Press).
19.
Hardebo JE: The involvement of trigeminal substance P neurons in cluster headache. A hypothesis. Headache 24:294-304, 1984.
20.
Judd A, Parker J, Jemmer FA: The role of Noradrenaline, Dopamine and 5-Hydroxytryptamine in the hyperactivity response resulting from the administration of tranylcypromine to rats pretreated with Lithium or Rubidimm. Psychopharmacologia 1:73-78, 1975.
21.
Samuel D, Gottesfeld Z: Lithium, mania, depression and the chemistry of the brain. Endeavour 32:122-126, 1973.
22.
Friedmann E, Wang Hy: Effect of chronic lithium treatment on 5-Hydroxytryptamine and release of 5-(3H)Hydroxytryptamine from rat brain corticol, hyppocampal and hypothalamic slices. J Neurochem 50:195-201, 1988.
23.
Swann AC, Heninger GR, Marini JL, Sheard MH, Mass JW: Lithium effects on high-affinity tryptophan uptake: evidence against a stabilization mechanism. Brain Res 194:287-292, 1980.
24.
Kripke DF, Judd LL, Hubbard B, Janowsky DS, Huey LY: The effect of lithium carbonate on the circadian rhythm of sleep in normal human subjects. Biol Psych 14:545-548, 1979.
25.
Fanciullacci M, Pietrini U, Boccuni M, Gatto C, Cangi F: Does lithium balance the neuronal bilateral asymmetries in cluster headache? Cephalalgia 3, suppl 1:85-87, 1983.
26.
Bussone G, Sinatra MG, Boiardi A, Frediani F, La Mantia L, Lamperti E, Peccarisi C: Brainstem auditory evoked potentials. (BAEPs) in cluster headache (CH): New aspects for a central theory. Headache 26:67-69, 1986.
27.
Peselow ED, Dummer DL, Fieve RR, Lautim A: Lithium prophylaxis of depression in unipolar, bipolar II and cyclothymic patients. Am J Psychiatry 139:747-752, 1982.
28.
Aragon MC, Herrero E, Gimenez C: Effects of systemically administered lithium on tryptophan transport and exchange in plasma-membrane vescicles isolated from rat brain. Neurochemical Research 12:439-444, 1987.
29.
Giannini AJ, Taraszewski R, Loiselle RH: Verapamil and Lithium in maintenance therapy of manic patients. J Clin Pharmacol 27:980-982, 1987.
30.
Dubousky SL, Franks RD, Lifshitz M, Coen P: Effectiveness of verapamil in the treatment of manic patients. Am J Psychiatry 139:502-504, 1982.
31.
Murphy KMM, Gould RJ, Largent BL, Snyder SH: A unitary mechanism of calcium antagonist drug action. Proc Natl Acad Sci USA 80: 860-864, 1983.
32.
Meyer JS, Nance M, Walker M, Zetusky WS, Dowell RE Jr: Migraine and cluster headache treatment with calcium antagonists supports a vascular pathogenesis. Headache 25:358-367, 1985.
33.
Meyer JS, Hardenberg J: Clinical effectiveness of calcium entry blockers in prophylactic treatment of migraine and cluster headache. Headache 23:266-277, 1983.
34.
Thayer SA, Welcome M, Chabra A, Fairhurst AS: Effects of dihydropiridim calcium channel blocking drugs on rat brain muscarinic and alpha-adrenergic receptors. Biochem Pharmacol 34:175-180, 1985.
35.
EI-Fakhany E, Richelson E: Effect of some calcium antagonists on muscarinic receptor mediated cyclic GMP formation. J Neurochem 40:705-710, 1983.
36.
Ohashi M, Kamai R, Takayamagi I: Do D 600 and diltiazem interact with serotonin receptors in rabbit vascular tissue? J Pharmacol Exp Ther 233:830-835, 1985.
37.
Taylor JE, Defeudis EU: Inhibition of (3H) spipirone binding to 5-HT2 receptors of rat cerebral cortex by the calcium antagonists verapamil and D 600. Eur J Pharmacol 106:215-216, 1984.
38.
Atlas D, Adler M: Alpha-adrenergic antagonists as possible calcium channel inhibitors. Proc Natl Acad Sci USA 78:1237-1241, 1981.
39.
Motulsky HJ, Snavely MD, Hughes RJ, Insel PA: Interaction of verapamil and other calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors. Circ Res 52:226-231, 1983.
40.
Maisel AS, Motulsky HJ, Insel PA: Hypothension after guanidine plus verapamil: possible additive competition at alpha-adrenergic receptors. N Engl J Med 312:167-170, 1985.
41.
Rezvani AH, Beleslin DB, Myres RD: Neuroanatomical mapping of hypothalamic regions mediating verapamil hyper and hypothermia in cats. Brain Res Bull 17:249-254, 1986.
42.
Pillai NP, Ross DH: Activation of dihidropyridine receptors differentially regulates temperature responses in rat. Pharmacol Biochern Behav 25:549-554, 1986.
43.
Kavaliers M: Calcium channel blockers inhibit the antagonist effects of Phe-Met-Arg-Phe-amide (FMRF-amide) on morphine and stress-induced analgesia in mice. Brain Res 415:380-385, 1987.
44.
Hotta I, Yamawaki S, Segawa T: Long-term lithium treatment causes serotonin receptor down-regulation via serotonergic presynapses in rat brain. Neuropsychobiology 16:19-26, 1986.
45.
Basbaum A, Fields HL: Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 7:309-338, 1984.
46.
Dickenson AM, Goldsmithe: Evidence for a role of 5-hydro-xytryptamine in the responses of rat raphe magnus neurones to peripheral noxious stimuli. Neuropharmacology 25:863-868, 1986.
47.
Wigdor S, Wilcox GL: Control and systemic morphine-induced antinociception in mice: contribution of descending serotonergic and noradrenergic pathways. J Pharmacol Exp Ther 242:90-95, 1987.
G. Bussone,* M. Leone,* C. Peccarisi,* G. Micieli,** F. Granella,*** M. Magri,**** G.C. Manzoni,*** and G. Nappi** *Headache
Centre, C. Besta Neurological Institute of Milan, Italy. of Neurology, University of Pavia, Italy. ***Clinic of Neurology, University of Parma, Italy. ****Medical Department, Knoll Spa of Milan, Italy. **Clinic
Reprint requests to: Dr. Gennaro Bussone, Istituto Neurologico "C. Besta," Via Celoria, 11, 20133 Milano (Italy). Accepted for Publication: May 6, 1990. SYNOPSIS
Chronic Cluster Headache (CCH) treatment is troublesome; since there are no pain-free periods, it must be continuous. The most effective CCH prophylactic drug today is lithium carbonate but long-term use of this drug is limited by the possibility of side effects. Recently, calcium antagonists have been successfully employed to prevent migraine, and preliminary studies also indicate that verapamil in particular is an efficacious treatment for CCH. We have conducted a multicenter trial employing a double-dummy, double blind, cross-over protocol, comparing verapamil with the established efficacy of lithium carbonate, in preventing CCH attacks. Both lithium carbonate and verapamil were effective in preventing CCH but verapamil caused fewer side effects and had a shorter latency period. We did not observe any correlation between plasma levels of the two drugs and their clinical efficacy. Both the drugs tested here may exert their effect by restoring a normal inhibitory tone to the pain modulating pathways from the trigemino-vascular system, a circuit putatively implicated in CCH. (Headache 30:411-417, 1990) INTRODUCTION
Therapy in cluster headache (CH) is particularly important in view of the rapidity of onset and the violence of the pain attacks, and the difficulty in controlling them with analgesics. Chronic cluster headache (CCH) is even more troublesome because there are no pain-free periods1 and treatment must be continuous. An enlargement of the therapeutic armamentarium for controlling this form of the illness would be highly desirable. The most effective CCH prophylactic today is lithium carbonate2 but long-term use of this drug is limited by the likelihood of side effects.3 Recently, calcium antagonists have been successfully employed to prevent migraine4,5,6,7,8,9 and preliminary studies also indicate that verapamil in particular is an efficacious treatment for CCH6; such studies in CCH have been of the open type, however, and there is a clear requirement for a double blind trial to verify or refute these initial findings. With this aim we conducted a multicentre double-blind trial comparing verapamil with the established efficacy of lithium carbonate. PATIENTS AND METHODS
Thirty subjects attending the Headache Centres at Milan, Pavia and Parma, and diagnosed as afflicted with chronic cluster headache according to International Headache Society (IHS) criteria,1 were included in the study. Subjects, all of whom gave their informed consent, were of both sexes and aged between 20 and 60 (Table 1). Specifically excluded were patients with cardiovascular, pulmonary, renal or liver conditions; so too were pregnant women and those taking oral contraceptives and prophylactic drugs for CH. Table 1 Clinical Aspects N 30 Age (yrs) 43 ± 11 Sex Male 27 Duration of Illness (yrs.) 9±5 Primary Chronic 18 Cluster Headache Secondary Chronic 12 Cluster Headache
Min 20 - Max 59 Female 3 Min 2 - Max 19
The trial was conducted employing a double-dummy, double-blind crossover protocol and lasted a total of 23 weeks (Figure 1). Each subject was administered wash-out/placebo for the first 2 weeks. Verapamil at 360 mg/day or lithium carbonate at 900 mg/day in 3 doses daily was given by randomized assignment starting from the 1st day of the 3rd week for 8 weeks. At the end of the 10th week all patients began a second wash-out/placebo phase, followed, commencing the 1st day of the 13th week, by the second 8-week treatment period. In this second period, patients who had received verapamil in the first period received lithium, and vice-versa. The final wash-out/placebo period, lasting 3 weeks, began after the completion of the 20th week. On the 1st,
14th and 56th days of both treatment periods, and at the end of the 23 weeks of the trial, patients were given electrocardiograms (ECG) and blood and urine tests. Lithium and verapamil levels in blood were determined on the 14th and 56th day of each treatment period. Patients were allowed access to NSAIDs as required throughout the entire trial period. Analgesics consumption and the intensity, frequency and duration of attacks were recorded daily on a diary card. Statistical evaluation was performed by cross-over multi-variant analysis of variance of the headache index (HI) and analgesic consumption (AC). Correlation between serum drug levels and clinical efficacy was also analysed. RESULTS
Only 24 of the 30 patients completed the study; six dropped out because of poor compliance during the first placebo wash-out. Clinical Efficacy: Both lithium and verapamil produced significant improvements in HI and AC (p < 0.01 ) (Figures 2 and 3). Over 50% of patients receiving verapamil experienced a reduction in HI during the 1st week, while lithium produced an HI improvement only in 37% of patients in the 1st week (Table 2). AC reduction was 58% in both treatment groups over the same period. Side Effects: 12% of patients receiving verapamil and 29% of patients receiving lithium reported side effects but these were never severe enough to warrant abandoning the treatment (Table 3). No significant changes in ECGs, blood pressure or blood and urine test results were observed over the trial period. Verapamil and Lithium Serum Levels: In 15 verapamil and 18 lithium patients it was possible to measure drug plasma levels at the 2nd and the 8th week of treatment (Figure 1). Mean verapamil level in blood on the 14th day of treatment was 83.5 ± 47 ng/I; on the 56th day it was 91.6 ± 68.8 ng/1. The corresponding values for lithium were 0.413 ± 0.1 meq/1 and 0.465 ± 0.1 meq/1 respectively; with neither drug was there a significant difference between the initial and final values. Dose/Effect Correlation: A numerical factor named delta expresses the differences in HI and drug plasma levels between the 2nd and the 8th week during each treatment. Relationships between delta HI and the corresponding deltas for drug plasma levels were investigated. Verapamil: no significant correlation was observed between verapamil and HI deltas (r = -0.05; P = ns; Figure 4). Lithium carbonate: a significant correlation was found between lithium and HI deltas (r = 0.74; P < 0.05; Figure 5, see discussion). DISCUSSION
In this study both lithium carbonate and verapamil were efficacious in preventing chronic cluster headache but verapamil caused fewer side effects (Table 3) and had a shorter latency period (Table 2). It is noteworthy that plasma levels of both drugs did not vary significantly from the 2nd to the 8th week of treatment, so that the significant correlation between
increase in plasma lithium (average 0.06 meq/1) and HI reduction is probably explained by the prolonged latency period for lithium effectiveness, a latency illustrated by the fact that by the end of the 1st week 50% of verapamil subjects showed clinical improvement but only 37% of lithium subjects did so. The mechanisms of action of neither lithium nor verapamil, in CCH prophylaxis, are known. Neither is the pathogenesis of CH understood.10,11 A "peripheral" source of pain in CH has not been proved and the idea of a vascular genesis in particular is now subject to considerable doubt.12,13,14,15,16,17 It seems ever more likely that the central nervous system (CNS) is involved in CH pathogenesis18 and that the vascular manifestations are merely epiphenomena.19 That lithium is a CH prophylactic is consistent with the central theory. The drug is known to interfere with CNS neurotransmitter metabolism,20,21 affecting particularly the serotoninergic system. Its long-term administration causes modifications to the pattern of serotonin release in the rat brain so that, for example, spontaneous release is reduced in the hippocampus and increased in the hypothalamus.22 Lithium also promotes tryptophan uptake in various cerebral areas, but not the cortex.23 Again, lithium is able to modulate the serotoninergic response to various stimuli, interfering with serotonin receptors or with their associated transduction systems.22 Lithium does not seem to modify noradrenaline release significantly.22 It is known that lithium is able to interfere with the physiological architecture of sleep,24 a fact of particular relevance when it is recalled that CH attacks tend to occur during sleep. Lithium has also been shown to reduce the asymmetric manifestations, of probable central origin, which occur in CH, normalising the response to tyramine eye-drops25 and restoring the asymmetries of the evoked potentials which are altered in that illness.26 The suggestion that lithium's therapeutic action in CH depends on its interference with certain CNS neuronal pathways is further supported by its efficacy
Table 2 Headache Index Improvement after Weeks Needed to Achieve the First Seven the Improvement of 50% Days of Treatment of the Treatment Patients N % Verapamil Lithium
12 9
50% 37%
1 2
in endogenous depression, which is of known central origin.27 It has been proposed that lithium acts here by restoring normal serotoninergic tone in the CNS.28 Verapamil too appears efficacious in the treatment of endogenous depression,29 as well as reducing other symptoms of central origin such as anxiety and disturbed behaviour.30 It is a phenylalkylamine derivative which exerts its calcium antagonist effect by interfering with the slow calcium channels (membrane structures called voltage operated channels) and thus modulates the calcium flux across cell membranes.31 Until recently it was thought that calcium antagonists only Table 3 Side Effects Verapamil
Lithium
Total Occurrence Constipation or Gastrointestinal Complaints Postural Hypotension, Cardiovascular Complaints Skin Rash Behavioural Changes Tremor Increased Diuresis Others
N 3
% 12%
N 7
% 29%
-
-
3
43%
2
67%
1
14%
-
-
-
-
2 1
67% 33%
3 1 2 2
43% 14% 29% 29%
affected cardiac and smooth muscle cells, so that a vascular mechanism of action for these drugs was proposed to account for their preventing headache.32 Other observations indicate, however, that calcium antagonists like verapamil act via a mechanism which
is not predominantly vascular. Variations in regional cerebral blood flow (rCBF) and cerebrovascular response to various stimuli were monitored in groups of CH and migraine patients while undergoing treatment with calcium antagonists, with the aim of observing correlations between cerebral hemodynamics and drug efficacy.32,33 Results showed that verapamil was more efficacious than other calcium antagonists in treating CH, but induced minimal changes in cerebral circulation which, in any event, were less than those produced by other calcium antagonist drugs. This poor correlation between vascular effects and clinical efficacy suggests that the cerebral vascular bed may not be the main site of action of verapamil in CH prophylaxis. Other studies indicate that verapamil is able to modulate central neuronal activity by several mechanisms: it may influence muscarinic,34,35 serotoninergic,36,37 dopaminergic and noradrenergic receptors.38,39,40 Verapamil seems to affect hypothalamic and noradrenergic functions in animals in vivo.41 Other systemically administered calcium antagonists also seem able to modify hypothalamic/ noradrenergic activity; the action appears mediated by rapid activation of specific hypothalamic enzymes.42 Of all the cerebral transmitter systems, it is the opiate system which is particularly sensitive to verapamil. When the drug is administered in high doses it is able to modify the analgesic effect of morphine. When administered systemically at low doses it modulates the inhibitory action that hypothalamic peptides exert on morphine-induced analgesia.43 In effect, it appears able to restore correct function of the analgesic system in the presence of an excess of these hypothalamic peptides-an action the drug exerts after a short latency period.43 The more rapid action of verapamil in CCH prophylaxis, noted also in the treatment of depression,29 compared with lithium, is therefore possibly explained by the different mechanisms of action of these drugs in the CNS. It may be that lithium acts mainly by restoring serotonergic tone,44 while verapamil's effect could be due to a neuromodulatory action on the opiate system.43 The role of the serotonergic and opiate systems on pain pathways is well understood.45,48,47 Both the drugs tested here might, therefore, exert their effect by restoring a normal inhibitory tone acting on sensory pain pathways. Acknowledgement: We wish to thank F. Macciardi MD (Psychiatry Institute, University of Milan) for statistical evaluation. REFERENCES
1.
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