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Calcitonin and prolactin serum levels in heroin addicts: Study on a methadone treated group
Drug and Alcohol Dependence Elsevier Scientific Publishers
20 (1987) 143 - 148 Ireland Ltd.
143
CALCITONIN AND PROLACTIN SERUM LEVELS ADDICTS: STUDY ON A METHADONE TREATED
W. SPAGNOLLI’, MIORIa
P. TORBOLIa,
M. MATTAREI*,
‘Ditisione Medica Trento (Italy!
1 and bLaboratorio
di Biochimica
G. De VENUTOa,
ed Ematologia
IN HEROIN GROUP
A. MARCOLLAb
-
Istituti
and R.
Ospedalieri.
(Received March 3rd, 1987) (Revision received June 12th, 1987)
SUMMARY
Serum calcitonin (CT) and prolactin (PRL) levels were determined in 21 heroin addicts in hospital treatment with methadone. After withdrawal of heroin the values of CT 112.4 -c 62.9 pglml, and PRL 19.1 -t 10.1 nglml were both significantly higher (P < 0.001) than in normal controls (62.2 f 43.8 pglml and 9.1 f 3.5 nglml, respectively). After withdrawal of methadone, i.e. 12 f 3.7 days after heroin withdrawal, CT values were 76.6 f 32.7 ng/ml (a significant level of P < 0.02 towards initial values). No correlation was noted between CT and PRL values.
Key words: Heroin - Dependence Calcitonin - Prolactin
- Withdrawal
- Methadone
-
INTRODUCTION
Recent findings regarding an analgesic effect of calcitonin (CT) [1,2] together with detection of immunoreactive CT-like material and specific receptors in the pituitary and in the central nervous system [3,4,5] suggest a possible involvement of CT in the neuroendocrine system. Experimental and clinical studies demonstrated that CT, as well as betaendorphin, has a central morphine-like analgesic effect which is not antagonised by naloxone, i.e. not dependent on opiate-endogenous receptors [2-71. Other studies showed that pharmacological doses of calcitonin can increase beta-endorphin serum levels [6]; by contrast, in heroin addicts, chronic consumption of opiates, can increase plasmatic levels of CT [8,9]. Also pharmacological doses of CT are able to inhibit the secretion of some 03’76.8716/87/$03.50 0 1987 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland
Ltd.
144
pituitary releasing hormones both basically and after specifics stimulation [lo - 121. In this study we evaluated calcitonin and prolactin (PRL) serum levels in a group of heroin addicts treated in hospital with methadone in tapered doses. MATERIALS
AND METHODS
We examined 21 subjects (18 women and 3 men, aged from 20 to 34 years, average 23 f 3.71subjects who had been heroin addicts for more than 2 years. Twelve of them declared a daily i.v. intake of ‘street heroin’ of 1 g or less and nine reported larger doses. Four subjects declared an occasionally high alcohol intake and nine a sporadic use of benzodiazepines. All subjects were admitted to a detoxication programme with tapered doses of methadone, from 35 or 15 mg to zero, for an average of 12 + 3.7 days. At admission, from 24 to 3 h after the last dose of heroin, blood samples were taken for the measurement of CT, PRL, morphine and for common laboratory tests. CT was again determined before discharge from hospital at the end of the methadone therapy (i.e. 24 h after the last administration). As control two groups of normal persons served: one of 36 subjects (31 men and 5 women aged from 17 to 37 years, average 24 -t 5.21for measurement of CT serum levels and one of 25 subjects (all females aged 20 to 30 years average 25 & 3.4) for measurement of PRL serum levels. Nobody in the two control groups showed signs of impaired liver, kidney or endocrine function, or had ever taken psychoactive drugs. Serum CT was assayed by a radioimmunological method (RIA) which employs an antiserum directed versus the 17-32 fraction of the sequence of human CT (Immune-Nuclear Co., Stillwater, U.S.A.). Serum PRL and morphine were measured using kits made by Biodata (RIA double Ab and Peg) and by Medical System (RIA coated tube). Routine tests were performed employing common automatized methods. The significance of the differences was calculated by Student’s t-test for paired and impaired observation. RESULTS
In the control subjects CT serum levels were between 15 and 254 pg/ml (average 62.2 & 43.81,PRL serum levels were from 3.2 to 16.5 nglml (average 8.1 -t 3.51. In heroin addicts CT levels, measured when heroin was withdrawn (from 24 to 3 h after the last dose), were between 48.8 and 355.6 pglml (average 112.4 f 62.91,at the end of the methadone therapy (i.e. 24 h after the last administration1 were from 17 to 161 pglml (average 76.6 + 32.7). We found the CT concentration significantly higher in the addicts’ group than in the controls (P < 0.001). CT levels fell significantly (P < 0.02) at the
145 p 0.001 D 0.02
140
I
n.s.
T
100
60
20
Pre-tr.
Post-tr. HEROIN
ADDICTS
Fig. 1. Calcitonin serum levels in 21 heroin addicts: (Pre-tr): mean values obtained from 24 to 3 h after the last dose of ‘street’ heroin; (Post-tr): values obtained 12 -c 3.7 days later, 24 h after the last dose of methadone. p 0.001
-
lHERO
N ADDICTS
CONTROLS
Fig. 2. Prolactin serum levels in heroin addicts (mean values obtained from 24 to 3 h after the last dose) and in 25 normal subjects.
146
end of the methadone therapy and were not different from those of the controls (Fig. 11. PRL serum levels in the heroin addicts (Fig. 21 measured from 24 to 3 h after heroin was withdrawn were between 7.5 and 39 nglml (average 19.1 + 101.1, i.e. significantly (P < 0.001) higher than in controls. No correlation was found between CT and PRL concentration. At admission a traceable morphine concentration was detected in 12 patients indicating an intake of heroin during the last 12 h [13]. Serum transaminase and/or alcaline phosphatase were slightly increased in 10 subjects, but none of them showed liver or kidney failure. The concentration of calcium and phosphate was in normal ranges in all patients (Table Il.
TABLE I SERUM CALCITONIN (CT) AND PROLACTIN ‘STREET’ HEROIN DOSE WAS WITHDRAWN METHADONE WERE ADMINISTERED
(PRI) IN 21 HEROIN ADDICTS, IN HOSPITAL AND TAPERED
IN WHOM DOSES OF
(Pre-tr) refers to values obtained from 24 to 3 h after the last dose of heroin; (Post-k) refers to values obtained 12 f 3.7 days later, 24 h after the last dose of methadone. Name
Age
Sex
(years) F.M. B.R. D.P.A. M.D. P.R. D.A.N. V.A. S.A. V.E. A.G. M.C. D.D. D.E.S. P.A.
22 24 20 20 22 23 21 22 20 34 25 23 22 23
B.D. G.A. Z.R. D.N. B.M. T.P. M.D.
31 22 20 20 25 20 32
ave. S.D.
23.4 2 4.0
F F F F F F F F F M F M F F F F M F F F F
Heroin (g)
CT pgtml (pre-tr.)
CT p&ml (post-tr.)
PRL ng/ml (pre-tr.1
1.0 2.5 1.0 1.5 1.5 1.0 1.0 0.5 1.5 1.0 1.0 0.4 1.5 3.5 0.3 1.5 1.0 1.0 2.5 2.0 1.0
355.6 78.0 172.0 69.0 101.0 106.7 155.8 95.0 79.7 71.2 121.5 48.8 139.0 92.5 85.3 111.6 105.0 70.3 91.7 108.7 101.0
104.4 45.7 69.0 161.0 72.0 92.8 120.0 50.1 75.0 68.6 52.0 17.0 70.5
21.0 27.5
112.4 2 62.9
69.5 67.5
26.0 9.0 38.0 39.0 10.0 25.0 12.5 8.5 7.5 12.5 21.0 9.0 17.5 10.0
51.9 70.3 90.5 92.0
20.0 33.0 16.5
75.8 + 30.9
19.1 k 10.0
147
DISCUSSION
Serum CT levels in heroin addicts were significantly higher than those of the controls and during the observation time they decreased to normal levels at the end of the methadone therapy. These results agree with the few data published [8,9]. Some authors, in order to obviate the circulating CT-like immunoheterogeneity, confirmed the increase of serum CT in these patients, also employing purifying techniques preceding RIA, and demonstrated an increase of the monomeric form of CT t91. Recently Tagliaro et al. [9] in a study on two groups of heroin addicts, one treated with methadone, and the other with clonidine, reported a normalisation of the serum CT concentration in the clonidine-treated group, whereas in the methadone-treated subjects the hormone levels fell significantly, but were still higher than in controls [9]. We found that at the end of the methadone therapy the high serum CT concentration returned to levels not significantly different from those of normal subjects. We measured again the hormone levels at the end of the methadone therapy, while in the aforementioned study CT levels were determined when the patients still received high doses of methadone. This can explain the disagreement between the two studies. The high CT concentration found in heroin addicts is not easy to explain. A decrease of the hormone clearance cannot be the reason, as neither the kidney, important organ for the catabolism of the CT [14,15], nor the liver showed clinical or biochemical signs of impaired function. Furthermore, no patient showed high levels of calcium or any evident alteration of the mineral metabolism which could justify a hypersecretion of CT. Opiates themselves might be involved in the increased production of CT. Morphine is a powerful blocker of dopamine receptors, whose administration can decrease CT concentration in patients with thyroid medullary carcinoma [1’7].A dopamine blockade might, therefore, have a stimulating effect on the secretion of the hormone [9]. Nevertheless changes in the release of other hormonal systems resulting from dopamine-blockade [16] could be involved in the increase of CT. High serum levels of PRL in opiate addicts have been reported [18,19] and the few data available indicate that PRL can increase CT concentration. An increase of plasma CT in patients suffering from prolactinoma was reported [20] and also an increased release of CT in a culture of thyroid medullary carcinoma after addition of PRL [21,22]. We found that PRL levels are higher in heroin addicts than in controls, but we did not observe any correlation with the CT plasma concentration. Further studies are needed to evaluate the meaning of these data using either a higher number of cases or a CT assay with more antibodies and/or purification techniques. Our results confirm nevertheless previous signals of a possible involvement of CT in changes of the endocrine system of heroin
148
addicts and furthermore point to the reversibility is withdrawn.
of the process when heroin
REFERENCES 1
6 7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
C.E. Fiore et al., Alcune attivitil extra schelettriche della calcitonina: effetto antalgico e neuromodulatore, in: C. Gennari and G. Segre (Eds.1, The Effects of calcitonin in Man, Masson, Milano, 1983, p. 291. A. Pecile et al., Experentia, 31 (19751332. L.J. Deftos et al., Clin. Endocrinol. Metab., 4’7 (19781457. J.A Fisher et al., Neurobiology, 78 (198117801. G. Luisetto et al., Presence of immunoreactive calcitonin in normal human pituitary glands and pituitary adenomas, in: M. Gennari (Ed.), Mineral Metabolism Research in Italy, Wichtig Editore, Milano, Vol. 1, 1980, pp. 17-20. C. Gennari, Calcitonin and bone metastases of cancer, in: A. Pecile, Calcitonin 80, Excerpta Medica-Endocrinology, Amsterdam, 1981, 277. P.C. Braga et al., Life Sci., 22 (19781971. F. Tagliaro et al., J. Endocrinol. Invest., 7 (19841331. F. Tagliaro et al., Drug Alcohol Depend., 16 (19851181. L. Cantalamessa et al., Metabolism, 27 (19781987. R. Isaac et al., J. Clin. Endocrinol Metab.. 50 (198011011. A. Petralito et al.. Horm. Metab. Res., 11 (19791641. D.R. Staski, D.J. Greenblatt and Lowenstein. Clin. Pharmacol. Ther., 24 (1978152. M. De Luise et al., J. Endocrinol., 53 (19721475. H.J. Wolfe, J. Endocrinol. Invest., 5 (19821423. G. Tolis. J. Hickey and H. Guyda, J. Clin. Endocrinol. Metab., 41 (1975) 797. S.C. Baylin et al., J. Clin. Endocrinol. Metab., 48 (19791408. P. Cushman, Drug Alcohol Depend., 5 (19801239. S. Lafisca et al., Drug Alcohol Depend., 8 (19811229. D. Ziliotto et al., J. Endocrin. Invest., 3 (1980171 N.H. Bell, Horm. Metab. Res., 7 (1975177. Y. Iwasaki et al., Life Sci., 25 (197911243.
20 (1987) 143 - 148 Ireland Ltd.
143
CALCITONIN AND PROLACTIN SERUM LEVELS ADDICTS: STUDY ON A METHADONE TREATED
W. SPAGNOLLI’, MIORIa
P. TORBOLIa,
M. MATTAREI*,
‘Ditisione Medica Trento (Italy!
1 and bLaboratorio
di Biochimica
G. De VENUTOa,
ed Ematologia
IN HEROIN GROUP
A. MARCOLLAb
-
Istituti
and R.
Ospedalieri.
(Received March 3rd, 1987) (Revision received June 12th, 1987)
SUMMARY
Serum calcitonin (CT) and prolactin (PRL) levels were determined in 21 heroin addicts in hospital treatment with methadone. After withdrawal of heroin the values of CT 112.4 -c 62.9 pglml, and PRL 19.1 -t 10.1 nglml were both significantly higher (P < 0.001) than in normal controls (62.2 f 43.8 pglml and 9.1 f 3.5 nglml, respectively). After withdrawal of methadone, i.e. 12 f 3.7 days after heroin withdrawal, CT values were 76.6 f 32.7 ng/ml (a significant level of P < 0.02 towards initial values). No correlation was noted between CT and PRL values.
Key words: Heroin - Dependence Calcitonin - Prolactin
- Withdrawal
- Methadone
-
INTRODUCTION
Recent findings regarding an analgesic effect of calcitonin (CT) [1,2] together with detection of immunoreactive CT-like material and specific receptors in the pituitary and in the central nervous system [3,4,5] suggest a possible involvement of CT in the neuroendocrine system. Experimental and clinical studies demonstrated that CT, as well as betaendorphin, has a central morphine-like analgesic effect which is not antagonised by naloxone, i.e. not dependent on opiate-endogenous receptors [2-71. Other studies showed that pharmacological doses of calcitonin can increase beta-endorphin serum levels [6]; by contrast, in heroin addicts, chronic consumption of opiates, can increase plasmatic levels of CT [8,9]. Also pharmacological doses of CT are able to inhibit the secretion of some 03’76.8716/87/$03.50 0 1987 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland
Ltd.
144
pituitary releasing hormones both basically and after specifics stimulation [lo - 121. In this study we evaluated calcitonin and prolactin (PRL) serum levels in a group of heroin addicts treated in hospital with methadone in tapered doses. MATERIALS
AND METHODS
We examined 21 subjects (18 women and 3 men, aged from 20 to 34 years, average 23 f 3.71subjects who had been heroin addicts for more than 2 years. Twelve of them declared a daily i.v. intake of ‘street heroin’ of 1 g or less and nine reported larger doses. Four subjects declared an occasionally high alcohol intake and nine a sporadic use of benzodiazepines. All subjects were admitted to a detoxication programme with tapered doses of methadone, from 35 or 15 mg to zero, for an average of 12 + 3.7 days. At admission, from 24 to 3 h after the last dose of heroin, blood samples were taken for the measurement of CT, PRL, morphine and for common laboratory tests. CT was again determined before discharge from hospital at the end of the methadone therapy (i.e. 24 h after the last administration). As control two groups of normal persons served: one of 36 subjects (31 men and 5 women aged from 17 to 37 years, average 24 -t 5.21for measurement of CT serum levels and one of 25 subjects (all females aged 20 to 30 years average 25 & 3.4) for measurement of PRL serum levels. Nobody in the two control groups showed signs of impaired liver, kidney or endocrine function, or had ever taken psychoactive drugs. Serum CT was assayed by a radioimmunological method (RIA) which employs an antiserum directed versus the 17-32 fraction of the sequence of human CT (Immune-Nuclear Co., Stillwater, U.S.A.). Serum PRL and morphine were measured using kits made by Biodata (RIA double Ab and Peg) and by Medical System (RIA coated tube). Routine tests were performed employing common automatized methods. The significance of the differences was calculated by Student’s t-test for paired and impaired observation. RESULTS
In the control subjects CT serum levels were between 15 and 254 pg/ml (average 62.2 & 43.81,PRL serum levels were from 3.2 to 16.5 nglml (average 8.1 -t 3.51. In heroin addicts CT levels, measured when heroin was withdrawn (from 24 to 3 h after the last dose), were between 48.8 and 355.6 pglml (average 112.4 f 62.91,at the end of the methadone therapy (i.e. 24 h after the last administration1 were from 17 to 161 pglml (average 76.6 + 32.7). We found the CT concentration significantly higher in the addicts’ group than in the controls (P < 0.001). CT levels fell significantly (P < 0.02) at the
145 p 0.001 D 0.02
140
I
n.s.
T
100
60
20
Pre-tr.
Post-tr. HEROIN
ADDICTS
Fig. 1. Calcitonin serum levels in 21 heroin addicts: (Pre-tr): mean values obtained from 24 to 3 h after the last dose of ‘street’ heroin; (Post-tr): values obtained 12 -c 3.7 days later, 24 h after the last dose of methadone. p 0.001
-
lHERO
N ADDICTS
CONTROLS
Fig. 2. Prolactin serum levels in heroin addicts (mean values obtained from 24 to 3 h after the last dose) and in 25 normal subjects.
146
end of the methadone therapy and were not different from those of the controls (Fig. 11. PRL serum levels in the heroin addicts (Fig. 21 measured from 24 to 3 h after heroin was withdrawn were between 7.5 and 39 nglml (average 19.1 + 101.1, i.e. significantly (P < 0.001) higher than in controls. No correlation was found between CT and PRL concentration. At admission a traceable morphine concentration was detected in 12 patients indicating an intake of heroin during the last 12 h [13]. Serum transaminase and/or alcaline phosphatase were slightly increased in 10 subjects, but none of them showed liver or kidney failure. The concentration of calcium and phosphate was in normal ranges in all patients (Table Il.
TABLE I SERUM CALCITONIN (CT) AND PROLACTIN ‘STREET’ HEROIN DOSE WAS WITHDRAWN METHADONE WERE ADMINISTERED
(PRI) IN 21 HEROIN ADDICTS, IN HOSPITAL AND TAPERED
IN WHOM DOSES OF
(Pre-tr) refers to values obtained from 24 to 3 h after the last dose of heroin; (Post-k) refers to values obtained 12 f 3.7 days later, 24 h after the last dose of methadone. Name
Age
Sex
(years) F.M. B.R. D.P.A. M.D. P.R. D.A.N. V.A. S.A. V.E. A.G. M.C. D.D. D.E.S. P.A.
22 24 20 20 22 23 21 22 20 34 25 23 22 23
B.D. G.A. Z.R. D.N. B.M. T.P. M.D.
31 22 20 20 25 20 32
ave. S.D.
23.4 2 4.0
F F F F F F F F F M F M F F F F M F F F F
Heroin (g)
CT pgtml (pre-tr.)
CT p&ml (post-tr.)
PRL ng/ml (pre-tr.1
1.0 2.5 1.0 1.5 1.5 1.0 1.0 0.5 1.5 1.0 1.0 0.4 1.5 3.5 0.3 1.5 1.0 1.0 2.5 2.0 1.0
355.6 78.0 172.0 69.0 101.0 106.7 155.8 95.0 79.7 71.2 121.5 48.8 139.0 92.5 85.3 111.6 105.0 70.3 91.7 108.7 101.0
104.4 45.7 69.0 161.0 72.0 92.8 120.0 50.1 75.0 68.6 52.0 17.0 70.5
21.0 27.5
112.4 2 62.9
69.5 67.5
26.0 9.0 38.0 39.0 10.0 25.0 12.5 8.5 7.5 12.5 21.0 9.0 17.5 10.0
51.9 70.3 90.5 92.0
20.0 33.0 16.5
75.8 + 30.9
19.1 k 10.0
147
DISCUSSION
Serum CT levels in heroin addicts were significantly higher than those of the controls and during the observation time they decreased to normal levels at the end of the methadone therapy. These results agree with the few data published [8,9]. Some authors, in order to obviate the circulating CT-like immunoheterogeneity, confirmed the increase of serum CT in these patients, also employing purifying techniques preceding RIA, and demonstrated an increase of the monomeric form of CT t91. Recently Tagliaro et al. [9] in a study on two groups of heroin addicts, one treated with methadone, and the other with clonidine, reported a normalisation of the serum CT concentration in the clonidine-treated group, whereas in the methadone-treated subjects the hormone levels fell significantly, but were still higher than in controls [9]. We found that at the end of the methadone therapy the high serum CT concentration returned to levels not significantly different from those of normal subjects. We measured again the hormone levels at the end of the methadone therapy, while in the aforementioned study CT levels were determined when the patients still received high doses of methadone. This can explain the disagreement between the two studies. The high CT concentration found in heroin addicts is not easy to explain. A decrease of the hormone clearance cannot be the reason, as neither the kidney, important organ for the catabolism of the CT [14,15], nor the liver showed clinical or biochemical signs of impaired function. Furthermore, no patient showed high levels of calcium or any evident alteration of the mineral metabolism which could justify a hypersecretion of CT. Opiates themselves might be involved in the increased production of CT. Morphine is a powerful blocker of dopamine receptors, whose administration can decrease CT concentration in patients with thyroid medullary carcinoma [1’7].A dopamine blockade might, therefore, have a stimulating effect on the secretion of the hormone [9]. Nevertheless changes in the release of other hormonal systems resulting from dopamine-blockade [16] could be involved in the increase of CT. High serum levels of PRL in opiate addicts have been reported [18,19] and the few data available indicate that PRL can increase CT concentration. An increase of plasma CT in patients suffering from prolactinoma was reported [20] and also an increased release of CT in a culture of thyroid medullary carcinoma after addition of PRL [21,22]. We found that PRL levels are higher in heroin addicts than in controls, but we did not observe any correlation with the CT plasma concentration. Further studies are needed to evaluate the meaning of these data using either a higher number of cases or a CT assay with more antibodies and/or purification techniques. Our results confirm nevertheless previous signals of a possible involvement of CT in changes of the endocrine system of heroin
148
addicts and furthermore point to the reversibility is withdrawn.
of the process when heroin
REFERENCES 1
6 7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
C.E. Fiore et al., Alcune attivitil extra schelettriche della calcitonina: effetto antalgico e neuromodulatore, in: C. Gennari and G. Segre (Eds.1, The Effects of calcitonin in Man, Masson, Milano, 1983, p. 291. A. Pecile et al., Experentia, 31 (19751332. L.J. Deftos et al., Clin. Endocrinol. Metab., 4’7 (19781457. J.A Fisher et al., Neurobiology, 78 (198117801. G. Luisetto et al., Presence of immunoreactive calcitonin in normal human pituitary glands and pituitary adenomas, in: M. Gennari (Ed.), Mineral Metabolism Research in Italy, Wichtig Editore, Milano, Vol. 1, 1980, pp. 17-20. C. Gennari, Calcitonin and bone metastases of cancer, in: A. Pecile, Calcitonin 80, Excerpta Medica-Endocrinology, Amsterdam, 1981, 277. P.C. Braga et al., Life Sci., 22 (19781971. F. Tagliaro et al., J. Endocrinol. Invest., 7 (19841331. F. Tagliaro et al., Drug Alcohol Depend., 16 (19851181. L. Cantalamessa et al., Metabolism, 27 (19781987. R. Isaac et al., J. Clin. Endocrinol Metab.. 50 (198011011. A. Petralito et al.. Horm. Metab. Res., 11 (19791641. D.R. Staski, D.J. Greenblatt and Lowenstein. Clin. Pharmacol. Ther., 24 (1978152. M. De Luise et al., J. Endocrinol., 53 (19721475. H.J. Wolfe, J. Endocrinol. Invest., 5 (19821423. G. Tolis. J. Hickey and H. Guyda, J. Clin. Endocrinol. Metab., 41 (1975) 797. S.C. Baylin et al., J. Clin. Endocrinol. Metab., 48 (19791408. P. Cushman, Drug Alcohol Depend., 5 (19801239. S. Lafisca et al., Drug Alcohol Depend., 8 (19811229. D. Ziliotto et al., J. Endocrin. Invest., 3 (1980171 N.H. Bell, Horm. Metab. Res., 7 (1975177. Y. Iwasaki et al., Life Sci., 25 (197911243.