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Majid Mahmoodi, PhD,5 Stefan P. Kruszewski, MD6. 1Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran. 2Department of ...
The American Journal on Addictions, 23: 48–52, 2014 Copyright © American Academy of Addiction Psychiatry ISSN: 1055-0496 print / 1521-0391 online DOI: 10.1111/j.1521-0391.2013.12062.x

Serum Biochemical Parameters Following Heroin Withdrawal: An Exploratory Study Kouros Divsalar, MSc,1 Manzumeh Shamsi Meymandi, PharmD,1,2 Mohammadreza Afarinesh, MSc,1,3 Mahdi Mahmoudi Zarandi, BSc,4 Tahereh Haghpanah, MSc,1 Fariborz Keyhanfar, PhD,2 Majid Mahmoodi, PhD,5 Stefan P. Kruszewski, MD6 1

Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran 3 Faculty of Medicine, Shahid Beheshty University of Medical Sciences, Tehran, Iran 4 Kerman University of Medical Sciences, Kerman, Iran 5 Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran 6 Private Practice and Associates, P.C., Harrisburg, Pennsylvania 2

Background: Long‐term consumption of opioid compounds, even after withdrawal, affects serum biochemical parameters. Investigating these alterations is a new approach in substance abuse studies. Method: This study investigated clinical laboratory results in men who are currently active, recently abstinent and non‐heroin users. Participants (N ¼ 240) of this matched cohort study included heroin dependent men referred for abstinence treatment, volunteer men who did not abuse opioids matched for age, sex, body mass index, and educational level (control group). The groups were further sub‐ divided for analysis into (a) continuous heroin users for more than 2 years (N ¼ 70), the dependent group; (b) heroin abusers with 1 month abstinence period (N ¼ 70), identified as ex‐heroin dependents; and (c) a matched, non‐dependent control group (N ¼ 100). All participants were tested for fasting blood sugar (FBS), sodium, potassium, calcium, uric acid (UA), blood urea nitrogen (BUN), creatinine, total cholesterol, triglycerides (TGs), total protein, fibrinogen, and prothrombin. Results: Compared to the control group, ex‐heroin dependents showed decreased FBS and significantly higher sodium, creatinine, and cholesterol levels. Compared to the heroin dependent group, the ex‐heroin dependents showed significant differences in FBS, sodium, calcium, creatinine, UA, and thrombin time. No significant differences were noted between ex‐heroin dependents and controls in potassium, calcium, UA, BUN, TGs, total protein, and thrombin time. Conclusion: These results demonstrate altered laboratory markers in long‐term heroin dependents as well as ex‐heroin dependents and suggest the need for further identification, population distribution, and etiological understanding of these biomarkers in individuals who have abused heroin. (Am J Addict 2014;23:48–52)

Received February 11, 2012; revised January 15, 2013; accepted January 17, 2013. Address correspondence to Dr. Manzumeh Shamsi Meymandi, Kerman Neuroscience Research Center, Jahad Blvd., Ebnesina Avenue, P.O. Box 76198‐13159, Kerman, Iran. E‐mail: [email protected]; [email protected]. 48

INTRODUCTION Substance abuse and its resulting economic, social, and health injuries have placed narcotic drugs as one of the four major global problems. Millions of dollars of governments’ budgets are spent for struggling against this problem every year. For this reason, researches about etiology, prevention, and treatment of substance abuse are increasing.1 Long‐term consumption of narcotic drugs causes more vulnerability to various diseases that affect both the consumer and the society. These diseases and injuries might continue even after drug abstinence, and not only have significant roles in the process of detoxification and health status of the affected individuals but also are a great burden for society. Therefore, identification of these problems, especially through noninvasive diagnostic methods like measuring serum biochemical parameters, is a novel approach in the improvement of health status of abstinent abusers and society. After drug abstinence, heroin‐dependents not only face social problems but also struggle with injuries and disorders resulting from long‐term consumption of substances and drug abstinence. Identification of these injuries and attempts for relieving them decrease the severity of injury and also the probability of relapse. In general, opioids alter the function of various body organs and systems like kidney, liver, central nervous system, and endocrine system leading to some metabolic and hemodynamic alterations.2,3 Heroin dependency significantly decreases the levels of some biochemical factors such as serum calcium and total cholesterol, but has no significant effect on fasting blood sugar (FBS), blood urea nitrogen (BUN), sodium (Naþ), potassium (Kþ), uric acid (UA), triglyceride (TG), creatinine, and total protein.4 Opioids consumption may also lead to osteoporosis not only through decreasing blood calcium but

also by inducing hormonal alterations.4–6 In different studies, decreased level of total cholesterol, LDL (low‐density protein), HDL (high‐density protein), and TG levels have been observed among heroin dependents.4,6,7 Moreover, while in opium consumers hemoglobin adult 1c (HbA1c) increases and plasma cholesterol and HDL levels decrease,8 continuous methadone consumption for the purpose of drug abstinence causes no change in cholesterol level and even modifies HbA1c level.9 Therefore, as it is seen, there are different reports about the effects of opioids abuse on blood biochemical parameters. In fact, drug abstinence following long‐term opioids use is always associated with significant physiologic alterations that some of them remain even for a long time and make the individual vulnerable to various disorders; for example, 1 month after heroin withdrawal, the numbers of monocytes and HGB (hemoglobin), HCT (hematocrit), MCH (mean cell hemoglobin), and MCHC (mean cell hemoglobin concentration) levels have shown significant differences in comparison to the corresponding values in non‐addicts.10 It has been also reported that most immune system parameters are suppressed following heroin withdrawal.11 The effects on bone density and dental diseases are among other problems of ex‐heroin users.12 The results of these mentioned studies together with alterations seen after withdrawal period in drug abusers9–11 encouraged the authors to perform an exploratory study about serum biochemical parameters and coagulation factors of heroin‐ dependents undergoing drug abstinence. Therefore, the present study can be considered as a novel attempt in determining alterations of several major biochemical parameters in the serum of ex‐heroin users undergoing drug abstinence.

solid–liquid column and thin layer chromatography (Acon & Baharafshan Co., Tehran, Iran). Opioids detection test (just screening test or RSA by rapid immune‐chromatography) were performed on the urine samples of controls and ex‐heroin users to reject any opium consumption. The present study had been approved by Ethical Committee of Kerman University of Medical Sciences (EC/KNRC/89‐42). After explaining the aims of study for participants and obtaining their written consent, their information including age, type of consumed drug, date of last consumption, and duration of drug consumption was recorded. Then, blood and urine samples were obtained before breakfast, when participants had undergone at least 8 hours of NPO (Latin for nothing by mouth). After assigning codes to samples, they were analyzed by blind researchers for measuring biochemical parameters.4,10,13 The intended parameters were determined by applying the following methods: sodium (Naþ) and potassium (Kþ): flame photometric method (standard flame photometer instrument); calcium (Ca2þ): cresolphethalein complex method (Darmankaw Co., Tehran, Iran); UA: phosphotangstate method (Zistchimi Co., Tehran, Iran); creatinine: Jaffe method (Pars Azmoon Co., Tehran, Iran); FBS, blood urine nitrogen (BUN), cholesterol, and TG: photometric and enzymatic methods, GPO‐PAP (Pars Azmoon Co. and Zistchimi Co.); total protein: end point calorimetric method (Zistchimi Co.); fibrinogen and thrombin time: coagulametric methods. Data were expressed as mean  SEM, and analysis was performed through SPSS 11.5 software package. One‐way ANOVA and Tukey‐Kramer post hoc tests were applied for comparison of groups. Statistical significant level was considered as p < .05.

METHODS Participants of this cross‐sectional study were 240 heroin‐ dependent men with the age range of 25–45 years referred for quitting and controls. Those with continuous heroin consumption for more than 2 years (N ¼ 70) were considered as dependent group and those undergoing drug abstinence treatment for more than 1 month (N ¼ 70) were considered as ex‐heroin dependents group. A number of 100 volunteer male non‐dependents matched for age, sex, body mass index (BMI), and educational level were also selected as the control group. Only those heroin‐dependents who smoked heroin and had DSM‐IV criteria were included into the study and those used heroin by injection or sniffing as well as multi‐substance abusers, recreational and trial consumers were excluded upon their self‐admission. Those with previous history of syphilis, hepatitis, AIDS, or any type of infectious diseases with defined clinical symptoms (like dermatological diseases) were excluded too. Continuous opioids consumption was confirmed using opioids diagnostic tests on urine samples of the heroin‐ dependent group. In the first step, a screening test was performed by rapid immune‐chromatography and in the second step, positive cases of primary screening underwent Divsalar et al.

RESULTS FBS did not show any significant difference in the heroin‐ dependent group compared to the control group, but it was significantly lower in the serum of ex‐heroin users in comparison to both control group (p < .001) and heroin‐ dependent group (p < .001). The concentration of Naþ in the serum of the heroin‐dependent group was not significantly different from that in the control group, but it was significantly higher in the ex‐heroin users group in comparison to both control and heroin‐dependent groups (p < .001 and p < .01, respectively). Kþ level was significantly lower in the heroin‐ dependent group as compared to the control group (p < .05), while no other difference was observed in comparison of groups. Ca2þ level in the heroin‐dependent group, but not in the ex‐heroin users group, was significantly lower than that in the control group (p < .05). The concentration of Ca2þ in the serum of ex‐heroin users was significantly higher than that in heroin‐dependents (p < .01). UA level in the heroin‐dependent group compared to the control group decreased significantly (p < .001) and while this parameter in ex‐heroin users showed no significant difference compared to the January–February 2014

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controls, it was significantly higher when compared to that in heroin‐dependents (p < .001). Although cholesterol level in the heroin‐dependent group was significantly lower compared to the control group (p < .001), it was significantly higher in the ex‐heroin users group in comparison to the heroin‐ dependent group (p < .001); in a way that it was close to the corresponding value in the control group. In ex‐heroin users, creatinine level was significantly higher in comparison to controls (p < .05) and heroin‐dependents (p < .001), while no difference was observed between heroin‐dependents and controls (Table 1). There was no significant difference among three groups in regard to BUN and TG levels. The blood coagulation factors of three groups are shown in Table 2. The amount of total protein and fibrinogen did not show significant difference among three groups. Prothrombin time in the heroin‐dependent group was significantly higher compared to both ex‐heroin dependents and the control group (p < .001), while it was similar in ex‐ heroin dependents and the control group (Table 2). DISCUSSION In the present study, biochemical parameters including FBS, Naþ, Kþ, Ca2þ, BUN, UA, TG, creatinine, cholesterol, total protein, fibrinogen, and thrombin time in the serum of a heroin‐ dependent group after undergoing a 1‐month withdrawal period were investigated. Based on our findings, long‐term consumption of heroin does not change FBS level, but withdrawal may decrease it. The reports in regard to the role of opioids in regulation of glucose homeostasis are controversial. In a study on rat, injection of opium solution increased serum glucose during the first two post‐injection hours.14 In a human study performed on diabetic patients (Type II), it has been reported that chronic opium consumption has no effect on FBS but it increases Hb1Ac.15 In another study on similar population, opium addiction decreased blood glucose temporarily but had no effect on Hb1Ac.16 Some researchers have claimed that these

effects are due to the alteration of plasma levels of adrenalin and noradrenalin, ACTH, cortisol, glucagon and insulin‐like growth factor.6,17 The observed hypoglycemia in ex‐heroin users might be due to the up‐regulation mechanisms of chronic consumption of opioids or due to the modifications in gene expression involved in glucose metabolism.17,18 According to Leu et al.17 opioid signaling system is involved in hypoglycemia. Chronic administration of opioids induced metabolic changes that are similar to those in diabetes type II, such as delayed and increased insulin response to glucose loads in heroin addicts.18 Nutritional status, duration of dependency and social life, or the presence of some hormonal disorders following substance abuse that affect kidney and liver could be the reason of hypoglycemia in ex‐heroin abusers. Opioids cause alterations in urinary output and urinary sodium exertion via neuronal and hormonal factors affecting kidney, central nervous system, and other organs.2 According to some studies, the concentration of some electrolytes like Kþ, Ca2þ, Mg2þ, Zn2þ, Fe2þ, Mn2þ, and Cl ions decreases in heroin‐dependents.4,19 In the present study, serum level of Na in dependent participants did not change, but it was significantly higher in ex‐heroin users as compared to the control group. The concentration of potassium ion in dependent and drug‐abstinent group was lower than that in the control group; even though, it was significant only in the heroin‐dependent group. These findings are similar to some other studies that have shown lower levels of K in heroin‐ dependent participants.19 While in chronic consumption of morphine, serum levels of sodium or potassium did not change significantly.6 The changes in concentration of Naþ and Kþ ions following long‐term consumption of heroin can be attributed to the structural alterations in adrenal cortex especially in zona glomerulosa and zona fasciculate cells.20 Obviously, this is not in contrast with elevation of Kþ and Naþ levels after administration of single high dose of opium in rats.14 This effect depends on chronic versus acute opioid administration or withdrawal.

TABLE 1. Serum levels of biochemical parameters in the three studied groups

Groups Biochemical parameters FBS (mg/dl) Naþ (mmol/l) Kþ (mmol/l) Ca2þ (mg/dl) Uric acid (mg/dl) BUN (mg/dl) Creatinine (mg/dl) Cholesterol (mg/dl) Triglyceride (mg/dl)

Control 86.7 139.3 4.6 9.37 5.3 15.7 .91 198.08 115.66

        

1.19 .2 .03 .07 .14 .42 .02 3.67 3.86

Heroin 81.65 138.3 4.16 8.86 4.05 15.67 .86 171.7 97.7

        

1.75 .64 .65* .86* .14*** .65 .02 8.7*** 8.76

Withdrawal 69.53 144.8 4.2 9.52 5.28 16.23 1.022 212 121

Data are presented as mean  SEM. *p < .05, ***p < .001 significant in comparison to the control group. ‡p < .01, §p < .001 significant in comparison to the heroin group.

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2.95***,§ .7***,‡ .05 .18‡ .14§ .5 .02*,§ 4.57*** 4.79

TABLE 2. Blood coagulation factors in the three studied groups

Total protein (mg/dl) Fibrinogen (mg/dl) Prothrombin time (sec)

Control

Heroin

Withdrawal

7.08  .03 3.73  .28 12.42  .14

6.92  .13 3.28  .8 15.09  .21*

6.86  .07 3.15  .07 12.33  .11**

Data are presented as mean  SEM. * p < .001 significant in comparison to the control group; **p < .001 significant in comparison to the heroin group.

Consumption of narcotic drugs inhibits hypothalamic– pituitary–gonadal axis and consequently decreases gonadal hormones such as testosterone, luteinizing hormone, follicle‐ stimulating hormone, and parathyroid hormone.5,6,21 Increase of osteoporosis incidence in both sexes has been observed in previous studies.5,22 Chronic heroin consumption is mentioned as one of the most important risk factors in osteoporosis‐related fractures.23 This is in line with significant lower concentration of serum calcium in heroin‐dependent participants in our study, while calcium level in ex‐heroin users was higher and close to its level in the control group. In another study on those undergoing heroin withdrawal, bone density has increased through increase of renal calcium clearance due to resorbtion processes.23 Intensive calcium clearance in ex‐ heroin addicts during withdrawal period has caused increased resorbtion in bone tissue.24 Another study has reported decreased bone density in dependents undergoing methadone‐therapy.25 Indeed, opium consumption can directly decrease bone density through its effects on osteogenesis process. Inhibition of osteoblasts growth in culture medium and reduction of serum osteocalcin are some direct effects of opium on osteogenesis.22 In the present study, UA in the serum of heroin‐dependent group was lower, while in ex‐heroin users its level was close to that in the control group. In a study on rats, it has been observed that long‐term consumption of morphine increases UA and creatinine levels.26 The increased level of these end‐products of nitrogen metabolism was associated with hepatotoxicity and nephrotoxicity properties of opioids increasing catabolism of purin nucleotides.26,27 Interestingly, in another study, like our study, heroin withdrawal had led to the returning of UA level to the normal level.27 Serum levels of total protein and fibrinogen did not show any change in heroin‐dependents or drug‐abstinents, but prothrombin time in heroin‐dependent group was higher compared to the control group and lower compared to the drug‐abstinent group. Also according to our previous study, electrophoretic profile of albumin and most of globulin does not change in heroin‐ dependents.13 Generally, long‐time use of opioids induces liver injuries. It has been recognized that glutathione increased by morphine is hepatotoxic and causes liver cells death.28 Gomez‐ Lechon et al.29 have observed that culture of human liver cells in proximity of .8–1 ml morphine and 3,6‐diacetyl morphine decreases glycogen and albumin production by 50%. Decrease of total protein level in dependents might be due to poor Divsalar et al.

nutrition in heroin‐dependents. Of course, liver function tests performed on serum of opium‐dependents in later years has shown increased levels of aminotransferase (SGPT, SGOT), lipoproteins, and fibrinogen.8 In regard to cholesterol and TGs levels, heroin‐dependents showed significantly lower serum cholesterol level and just the opposite in ex‐heroin users group this parameter was significantly higher as compared to the control group. The same pattern was observed for TG level but non‐significantly. Also in our previous study, lower levels of total cholesterol and HDL have been observed in heroin‐dependents.4 In other studies, serum lipids levels including total cholesterol, HDL, and TG in heroin‐dependents showed significant decrease.7,8 It is interesting to know that in diabetic opium‐dependents total cholesterol decreases although non‐significantly.15 In contrast, in patients with non‐malignant pain who received chronic intrathecal opioids, cholesterol, and TGs concentrations increased.6 This discrepancy might be attributed to different doses used by patients and heroin dependents. The alteration of cholesterol and TGs is not only due to metabolic changes but also can be the consequence of low levels of lipid, cholesterol and TG intake in heroin‐dependent individuals resulting mainly from their poor nutritional status. This study had several limitations. The participants had not been screened for comorbid psychiatric disorders, such as depression which may affect their appetite and consequently biochemical parameters, or noninfectious diseases such as hypertension (hydrochlorothiazide affects potassium level). Moreover, individuals who abuse drugs often take a wide spectrum of psychoactive substances prescribed during and after drug quit. Since this was a naturalistic study, those substances were not controlled. How those unknown substances or concurrent medications might therefore affect biochemical parameters cannot be known. Despite screening all opioid users by urine drug testing, what our sub‐populations were using is an open question. A standardized interview method (SCID or MINI) might screen substance use and psychiatric disorders. In Iran where drug abuse is a concept that has both disease and criminal manifestations, we would not expect our participants to declare their substances or cooperate honestly with our protocol. Moreover, our study is limited due to our sample population and could not be generalized to other sub‐populations in Iran or other nations. Since our study was cross‐sectional, we would not anticipate the standard expected as if it was prospective. January–February 2014

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Despite the above limitations, we are able to conclude in the present study that abstinence from heroin consumption results in serum alterations of glucose, sodium, calcium, UA, creatinine, and prothrombin. Identification of these basic laboratory values may assist clinical care of heroin users and abstinents. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

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