|
|
||||
|
Published by : PROFESSIONAL MEDICAL PUBLICATIONS |
||||
|
ISSN 1681-715X |
||||
|
||||
|
|
||||
|
- |
||||
|
ORIGINAL ARTICLE |
||||
|
- |
||||
|
Volume 25 |
July - September 2009 |
Number 4 |
||
|
|
||||
|
||||
Comparison of the efficacy and safety of Chlorpromazine
with Verapamil for the treatment of acute opioid
abstinence syndrome
Munawar Alam Ansari1, Zahida Memon2, Shahida P. Ahmed3, Mehar Ali4
ABSTRACT
Objective: To compare the efficacy and safety of chlorpromazine with Verapamil in patients with Acute opioid Abstinence Syndrome.
Methodology: Single blind comparative clinical trial was conducted at Department of Pharmacology, BMSI, JPMC, Karachi, over the period of one year. Forty opiate-dependent subjects were chosen at random who were in search of opioid abstinence treatment. All patients were grouped into two groups, group-I received chlorpromazine 150 mg/day and group-II received Verapamil 120mg/day in divided doses. Every patient completed the management plan while admitted in the hospital for 10 days.
Results: The chlorpromazine showed decreased efficacy and safety, whereas verapamil showed clinically pertinent decline in the subjective symptoms of acute opioid abstinence syndrome.
Conclusion: The study showed Verapamil is superior to chlorpromazine in the treatment of opioid abstinence syndrome indicated by better reduction of withdrawal symptom scores, excessive opioid urinary excretion and lees side effects. The superiority of verapamil over chlorpromazine in controlling opioid abstinence syndrome may indicate that calcium is involved in the initiation and development of opioid abstinence syndrome.
KEY WORDS:
Opioid abstinence syndrome, Chlorpromazine, Verapamil.Pak J Med Sci July - September 2009 Vol. 25 No. 4 641-645
How to cite this article:
Ansari MA, Memon Z, Ahmed SP, Ali M. Comparison of the efficacy and safety of Chlorpromazine with Verapamil for the treatment of acute opioid abstinence syndrome. Pak J Med Sci 2009;25(4):641-645.
1. Dr. Munawar Alam Ansari, Ph.D,
Associate Prof., Dept. of Pharmacology & Therapeutics,
Liaquat University of Medical & Health Sciences,
Jamshoro – Pakistan.
2. Dr. Zahida Memon, Ph.D,
Professor, Dept. of Pharmacology,
Sind Medical College, Karachi-Pakistan.
3. Dr. Shahida P. Ahmed, Ph.D
Professor, Dept. of Pharmacology, University of Karachi.
4. Dr. Mehar Ali, M.Phil,
(Rtd.) Professor & Chairman Pharmacology,
Basic Medical Sciences Institute (BMSI),
Jinnah Postgraduate Medical Center, Karachi.
Correspondence
Dr. Munawar Alam Ansari, Ph.D
E-mail: dr_mnwr@yahoo.com
* Received for Publication: January 20, 2009
* Revision Received: June 11, 2009
* Revision Accepted: June 29, 2009
INTRODUCTION
Drug addiction is a chronic state characterized by obsessive behavioral anomaly.
1,2 Opioids are recognized to manipulate the function of central dopaminergic systems and an excellent accord be present on the conception that opiates stimulates the striatum circuits which get input from dopamine neurons and increases firing action of dopaminergic nerve terminals.3,4 As a result the dopamine receptors antagonist chlorpromazine at present is increasingly used for controlling opioid abstinence syndrome at various narcotic management centers which blocks the dopamine receptors in mesolimbic and mesocortical pathways of central nervous system.5,6 Subsequently it must restrain abstinence from opioids and may possibly be helpful for treatment of opioid abstinence syndrome.7On the other hand calcium plays an essential part in action of opioids.
8-11 There is evidently an opposite association among calcium and opiate action. Opiates reduce neurotransmitter discharge by means of slowing down the depolarization-induced entry of calcium in to neurons.4,12 Hence calcium influx may perhaps be one of the mechanisms of the activity of opioids, whereas the continual and persistent administration of morphine causes an amplified calcium entry, coupled with alterations in calcium uptake and binding.11-13 Such augmented content of calcium at the time of precipitated opioid removal, resulting in amplified neurotransmitter discharge and increased autonomic disparity during the opioid abstinence syndrome.14-16 Consequently the study was conducted to match up the efficacy and safety of verapamil with contemporary remedy chlorpromazine as management of acute opioid abstinence syndrome in patients.METHODOLOGY
This study was conducted in the department of Pharmacology and Therapeutics, Basic Medical Sciences Institute and Jinnah Postgraduate Medical Centre, Karachi. Each patient gave written approval to study team that required mandatory immediate withdrawal from opioids following hospital admission.
Study population: The forty chosen addicts diagnosed according to DSM IV diagnostic criteria
17 and looking for inpatient opioid abstinence management were enrolled in study. All the patients were admitted to the inpatient psychiatry wards for ten days. All those patients were excluded from study that had a prior history of major psychiatric complaint, existing addiction on alcohol or dependence on other drugs of abuse like hypnotics, heart and hepatic diseases. All patients included in the study were male and wished-for holding up the use of opioidsStudy design: Patients were randomly separated into two groups; group I (n=20) received Chlorpromazine; group II (n=20) received Verapamil. They were observed and rated for the existence or nonexistence of opioid abstinence symptoms expressed prior 24 hours by an observer. From day two of hospitalization, until discharge, an observer finished the opiate withdrawal questionnaire (OWQ), which contains 20 distinctive withdrawal symptoms, like, muscle cramps, flushing, joint pain, yawing, impatience, lacrimation, watery nose, chills, unwell stomach, sneezing, abdominal cramps, tetchiness, back pain, perspiration, dejected, insomnia, insecure, hot or cold flashes, irritable to noise, damp and clammy skin. Participants pointed out the extent to which they had practiced every symptom and then observer graded the intensity of the symptoms between 0- no symptom, 1- slight, 2- moderate, 3- quite a bit & 4- tremendous symptoms. The combined score for subject reported symptoms was obtained by totaling the scores of the individual symptoms simultaneously.
6,8,9,18,19Urine samples were collected on start, mid and closing of study, and tested for opioid by means of one- step dip and read chromatographic front line opiate strips, obtained from Boehringer Mannheim Pakistan.
6,8,9,18,19 The quantity of opioid in the urine was graded between 0-3 point ranges (Table-I). All patients had a bed rest on 2nd and 3rd day of hospitalization. Afterward from day 3 to day 9 the patients of group-I and group-II received 50mg of chlorpromazine and 40mg of Verapamil orally three times a day respectively. All patients were discharged from hospital on day 10 of study, when they were experiencing clinically negligible or no withdrawal symptoms.Statistical Analysis:
Complete data are expressed as means ± SEM. Differences among means of study days were tested for significance using the paired Student’s t-test. Data analysis was performed using the Statistical Program for Social Sciences (SPSS) 10.0 for windows. For all analyses, P values less than 0.05 was well thought-out significant.RESULTS
Forty eight patients as per procedure were enrolled in this study, in order to get the target sample of twenty patients for each of two groups. Eight patients of chlorpromazine group were dropped from study with the entire breakdown of 28.5%.
The fundamental characteristics of all patients in both groups were similar (Table-II). All had subjective symptoms of opioid withdrawal and urine samples showing positive outcome when tested with front line opiates dipsticks. Patients on chlorpromazine therapy experienced adverse effects and rate of recurrence of observed side effects were (45%). The experiential adverse effects were dryness of mouth (20%); blurred vision (5%), headache (10%) and postural hypotension (10%). At the same time symptomatic management like Aspirin 300mg three times a day for muscle ache, Diazepam 5mg for nocturnal sedation, Hyoscine 10mg three times a day for abdominal discomfort and Phenargon 10mg three times a day for nausea and vomiting were given to group-I & group-II patients on 3rd,4th,5th and 6th admission day.
In group-I an average score of withdrawal symptoms 15±0.205 was obtained on 2
nd day of admission and the score reaches to a highest point of 32.55±0.738 during the baseline phase that is on 3rd day of admission. Following chlorpromazine treatment the mean scores of withdrawal symptoms reduced very slowly and gradually. Accordingly the effects of chlorpromazine to drop off the symptoms of acute opioid abstinence syndrome were non- significant on day 4 and day 5, significant on day 6, while highly significant on day 7 to last day of admission. (Fig-1)
Even as in group-II patients an average score of symptoms 17.5.0±0.559 was obtained on 2nd day of admission that hit the uppermost point of 31.5±0.638 during the baseline phase that is on 3rd day of hospitalization. Subsequently Verapamil therapy showed superior cutback and highly significant decline in withdrawal symptoms score from very fist post- treatment day (Fig-1) and it did not show any drug related side effect during study duration.
Withdrawal symptoms were decreased in both groups, but the distinction among the groups was highly significant in favor of verapamil group from day 4 to day 10. (Table-III) Even as the significant difference in urinary excretion of opioid was observed in group-II patients when compared with group-I patients. (Table-I)
DISCUSSION
Clinically we need a standardized and secure course of therapy for opioid addicts, as addiction is highly prevalent in Pakistan. Conventionally opioid agonistic drugs like Methadone is a most frequent regiman for abstinence syndrome all over the world,
19 but it is banned in Pakistan and still concerned with abuse pattern. On the whole the major object of this study was to institute a safer non-opioid treatment option which is secure and not involved in the misuse potentials. To our knowledge this is the first and initial study, to compare the efficacy and safety of chlorpromazine with calcium channel blocker verapamil in the management of acute opioid abstinence syndrome. Though Mazurier et al7 has discussed the issue and compared chlorpromazine with morphine for the management of opioid abstinence syndrome in infants. However this study merely emphasized the comparison of duration of treatment for abstinence syndrome in neonates using chlorpromazine against morphine.The data of chlorpromazine therapy for its effectiveness and safety is inadequate. Our study established
no therapeutic advantage of chlorpromazine in acute opioid abstinence syndrome. The outcome of our study is strongly well-matched with the research of Caille and his co-workers,20 who tested the dopamine hypothesis in acute opioid abstinence syndrome in morphine dependent rats. While Daglish et al3 investigated the brain dopamine response in human opioid addicts. Both these studies proved that dopamine dose not play any vital role in abstinence syndrome in opioid dependent animals as well as humans. Subsequently these conclusions recommend that dopamine neurotransmission is not decisive for the initiation and precipitation of opioid withdrawal syndrome.While the novel verapamil treatment, , for abstinence syndrome proved to be appreciably superior than chlorpromazine therapy, in terms of declined withdrawal symptoms, excessive opioid urinary excretion as well as side effects were observed during ten days study.
Generally the verapamil treatment is safe, secure, well accepted and free of adverse effects. This study also indicates, highly significant, retention in treatment was in verapamil group, almost certainly due to entire decreased load of withdrawal symptoms particularly during preliminary post-treatment days as compared to chlorpromazine group.
CONCLUSIONS
This comparative clinical trail suggests that verapamil is significantly beneficial non opioid therapeutic option for the management of opioid withdrawal syndrome. The study showed the verapamil is superior to chlorpromazine in the treatment of opioid abstinence syndrome indicated by better reduction of withdrawal symptom scores, excessive opioid urinary excretion and lees side effects. The superiority of verapamil over chlorpromazine in controlling opioid abstinence syndrome may indicate that calcium is involved in the initiation and development of opioid abstinence syndrome.
REFERENCES
1. Spiga S, Lintas A, Diana M. Addiction and cognitive functions. Ann N Y Acad Sci 2008;1139:299-306.
2. Ivan D, Montoya, Frank Vocci. Novel medications to treat addictive disorders. Curr Psychiatry Rep 2008;10(5):392-398.
3. Danglish MR, Williams TM, Wilson SJ, Taylor LG, Eap CB, Augsburger M, et al. Brain dopamine response in human opioid addiction. Br J Psychiatry 2008;193(1):65-72.
4. Bailey CP, Connor M. Opioids: cellular mechanisms of tolerance and physical dependence.Curr Opin Pharmacol 2005;5(1):60-68.
5. Devto P, Flore G, Pira L, Diana M, Gessa GL. Co-release of noradrenaline and dopamine in the prefrontal cortex after acute morphine and during morphine withdrawal. Pschypharmacology (Berl) 2002;160(2):220-24.
6. Ansari MA, Ahmed SP, Kazi A. The role of d-2 receptor antagonist chlorpromazine in observer rated signs of acute opioid abstinence syndrome. J Basic Appl Sci 2007;3(1):39-42.
7. E Mazurier, G Camonie, A Grare, V Pinzani, JC Picaud. Comparison of chlorpromazine versus morphine hydrochloride for treatment of neonatal abstinence syndrome. Acta Paediatrica 2008;97(10):1358-1361.
8. Ansari MA, Mehar A. Calcium Channel blocker Verapamil: A non opioid treatment for acute opioid Abstinence syndrome. Pak J Med Sci. 2003;19(3):173-177.
9. Ansari MA, Ahmed SP, Mehar A. Calcium Channel blocker Verapamil: A non hormonal option for hot flashes management in patients with acute opioid abstinence syndrome. Pak J Med Sci 2007;33(3):353-357.
10. Ansari MA, Ahmed SP. Calcium channel blocker VERAPAMIL: A new intervention for high cholesterol levels in patients with PTSD. Turk Jem 2007;11:93-97.
11. Ansari MA, Ahmed SP, Memon Z. Dose calcium channel blocker verapamil decrease urinary VMA in Sympathoadrenal hyperactive patients with Posttraumatic Stress Disorder? Asian Pac J Trop Med 2008;1(4):36-39.
12. De Vries TJ, Shippenberg TS. Neural systems underlying opiate addiction. J Neurosci 2002;22:3321-3325.
13. Jaqe J. Opioid tolerance and dependence—do they matter? Eur J Pain 2005;9(2):157-162.
14. Maddux JF, Desmond DP. Addiction or dependence? Addiction 2000;95:661-665.
15. Tanq L, Shukla PK, Wanq LX, Wang ZJ. Reversal of morphine antinocieptive tolerance and dependence by the acute supraspinal inhibition of Ca(2+) calmodulin – dependent protein kinase II. J Pharmacol Exp Ther 2006;317(2):901-909.
16. Wang P, Chicka MC, Bhalla A, Richards DA, and Chapman ER. Synaptotagmin VII is targeted to secretory organelles in PC12 cells, where it functions as a high-affinity calcium sensor. Mol Cell Biol 2005;25(19):8693-702.
17. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th Ed: DSM-IV. Washington, D.C.: American Psychiatric Association, 1994.
18. AnsariMA, Wagan MA.Shaikh RA and Ali M. Role of clonidine in acute opioid abstinence syndrome. Pak J Med Sci 2001;17(3):163-168.
19. Ansari MA, Ahmed SP, Kazi A and Karim N. Role of a-2 agonist Clonidine in attenuation of Hot flashes in patients with Acute Opioid Abstinence Syndrome. Pak J Pharmacol 2005;22(2):47-51.
20. Caille S, Rodriguez-Arias M, Minarro J, Espejo EF, Cador M, Stinus L. Changes in dopaminergic neurotransmission do not alter somatic or motivational opiate withdrawal-induced symptoms in rats. Behav Neurosci 2003;117(5):995-629.