Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients

Anna Maria Aloisi, Ilaria Ceccarelli, Maria Carlucci, Annalisa Suman, Gianfranco Sindaco, Sergio Mameli, Valentina Paci, Laura Ravaioli, Giandomenico Passavanti, Valeria Bachiocco, Gilberto Pari, Anna Maria Aloisi, Ilaria Ceccarelli, Maria Carlucci, Annalisa Suman, Gianfranco Sindaco, Sergio Mameli, Valentina Paci, Laura Ravaioli, Giandomenico Passavanti, Valeria Bachiocco, Gilberto Pari

Abstract

Background: In male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anaemia and depression. Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available.

Methods: To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine (epidural route), we tested the administration of testosterone via a gel formulation for one year. Hormonal (total testosterone, estradiol, free testosterone, DHT, cortisol), pain (VAS and other pain questionnaires), andrological (Ageing Males' Symptoms Scale-AMS) and psychological (POMS, CES-D and SF-36) parameters were evaluated at baseline (T0) and after 3, 6 and 12 months (T3, T6, T12 respectively).

Results: The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12. Pain rating indexes (QUID) progressively improved from T3 to T12 while the other pain parameters (VAS, Area%) remained unchanged. The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time.

Conclusions: In conclusion, our results suggest that a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient's quality of life, an important clinical aspect of pain management.

Figures

Figure 1
Figure 1
Morphine dose assessment. Time course of the morphine dose at basal time (T0) and after 3, 6 and 12 months of testosterone replacement therapy (T3, T6 and T12, respectively) in patients participating in the entire study. The lines represent the time course of the individual patients numbered as in Table 1.
Figure 2
Figure 2
Serum total testosterone. Serum total testosterone (TT) values at basal time (T0) and after 3 (T3), 6 (T6) and 12 (T12) months of testosterone replacement therapy. The insert reports the TT levels at basal time (T0) and 1, 2 and 3 months from the beginning of testosterone replacement therapy (T1, T2 and T3, respectively) of the first four patients used to evaluate the time course of tissue androgen permeation. Data are mean ± SEM. * p < 0.05 vs T0.
Figure 3
Figure 3
Hormonal parameters evaluation. Serum dihydrotestosterone (DHT, A), estradiol (E2, B), DHT/T ratio (C), E/T ratio (D), bioavailable testosterone (BioT, E) and free testosterone (fT, F) values at basal level (T0) and after 3, 6 and 12 months of testosterone replacement (T3, T6 and T12, respectively). Data are mean ± SEM. * p < 0.05 vs T0.

References

    1. Daniell HW, Lentz R, Mazer NA. Opel-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency. J Pain. 2006;7:200–210. doi: 10.1016/j.jpain.2005.10.009.
    1. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic non cancer pain: a meta-analysis of effectiveness and side effects. CMAJ. 2006;174:1589–1594.
    1. Abs R, Verhelst J, Maeyaert J, Van Buyten JP, Opsomer F, Adriaensen H, Verlooy J, Van Havenbergh T, Smet M, Van Acker K. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215–2222. doi: 10.1210/jc.85.6.2215.
    1. Aloisi AM, Pari G, Ceccarelli I, Vecchi I, Ietta F, Lodi L, Paulesu L. Gender-related effects of chronic non-malignant pain and opioid therapy on plasma levels of macrophage migration inhibitory factor (MIF) Pain. 2005;115:142–151. doi: 10.1016/j.pain.2005.02.019.
    1. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377–384. doi: 10.1054/jpai.2002.126790.
    1. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008;9:28–36. doi: 10.1016/j.jpain.2007.08.005.
    1. Fraser LA, morrison D, Morley-Forster P, Paul TL, Tokmakejian S, Larry Nicholson R, Bureau Y, Friedman TC, Van Uum SH. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009;117:38–43. doi: 10.1055/s-2008-1076715.
    1. Ceccarelli I, De Padova AM, Fiorenzani P, Massafra C, Aloisi AM. Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats. Neuroscience. 2006;140:929–937. doi: 10.1016/j.neuroscience.2006.02.044.
    1. Amini H, Ahmadiani A. In vivo evidence for an increase in 5 alpha-reductase activity in the rat central nervous system following morphine exposure. Int J Dev Neurosci. 2005;23:621–626. doi: 10.1016/j.ijdevneu.2005.07.001.
    1. Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM. Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004;62:188–193.
    1. Straub RH, Cutolo M. Involvement of the hypothalamic-pituitary-adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum. 2001;44:493–507. doi: 10.1002/1529-0131(200103)44:3<493::AID-ANR95>;2-U.
    1. Harbuz MS, Perveen-Gill Z, Lightman SL, Jessop DS. A protective role for testosterone in adjuvant-induced arthritis. Br J Rheumatol. 1995;34:1117–1122. doi: 10.1093/rheumatology/34.12.1117.
    1. Gaumond I, Arsenault P, Marchand S. The role of sex hormones on formalin-induced nociceptive responses. Brain Res. 2002;958:139–145. doi: 10.1016/S0006-8993(02)03661-2.
    1. Aloisi AM, Ceccarelli I, Fiorenzani P, De Padova AM, Massafra C. Testosterone affects pain-related responses differently in male and female rats. Neurosci Lett. 2004;361:262–264. doi: 10.1016/j.neulet.2003.12.023.
    1. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89:2085–2098. doi: 10.1210/jc.2003-032006.
    1. Huskisson EC, Jones J, Scott PJ. Application of Visual-Analogue Scales to the measurement of functional capacity. Rheumatol Rehabil. 1976;15:185–187. doi: 10.1093/rheumatology/15.3.185.
    1. De Benedittis G, Massei R, Nobili R, Pieri A. The Italian Pain Questionnaire. Pain. 1988;33:53–62. doi: 10.1016/0304-3959(88)90203-5.
    1. Margolis RB, Tait RC, Krause SJ. A rating system for use with patient pain drawings. Pain. 1986;24:57–65. doi: 10.1016/0304-3959(86)90026-6.
    1. Saccò M. Validazione culturale e linguistica di un questionario per definire il deficit androgenico nell'invecchiamento maschile. G Gerontol. 2004;52:74.
    1. McNair DM. EdITS manual: profile of mood states. Educational and Industrial Testing Service. San Diego; 1971.
    1. Fontani G, Corradeschi F, Felici A, Alfatti F, Migliorini S, Lodi L. Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. Eur J Clin Invest. 2005;35:691–699. doi: 10.1111/j.1365-2362.2005.01570.x.
    1. Fava GA. Assessing depressive symptoms across cultures: Italian validation of the CES-D self-rating scale. J Clin Psychol. 1983;39:249–251. doi: 10.1002/1097-4679(198303)39:2<249::AID-JCLP2270390218>;2-Y.
    1. Bos MJ, Lindén T, Koudstaal PJ, Hofman A, Skoog I, Breteler MM, Tiemeier H. Depressive symptoms and risk of stroke: the Rotterdam Study. J Neurol Neurosur Psychiatry. 2008;79:997–1001. doi: 10.1136/jnnp.2007.134965.
    1. Apolone G, Mosconi P. The Italian SF-36 Health Survey: translation, validation and norming. J Clin Epidemiol. 1998;51:1025–1036. doi: 10.1016/S0895-4356(98)00094-8.
    1. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666–3672. doi: 10.1210/jc.84.10.3666.
    1. Fabbri A, Giannetta E, Lenzi A, Isidori AM. Testosterone treatment to mimic hormone physiology in androgen replacement therapy. A view on testosterone gel and other preparations available. Expert Opin Biol Ther. 2007;7:1093–1106. doi: 10.1517/14712598.7.7.1093.
    1. Ballantyne JC. Chronic pain following treatment for cancer: the role of opioids. Oncologist. 2003;8:567–575. doi: 10.1634/theoncologist.8-6-567.
    1. Delitala G, Giusti M, Mazzocchi G, Granziera L, Tarditi W, Giordano G. Participation of endogenous opiates in regulation of the hypothalamic-pituitary-testicular axis in normal men. J Clin Endocrinol Metab. 1983;57:1277–1281. doi: 10.1210/jcem-57-6-1277.
    1. Vuong C, Van Uum HM, O'Dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010;31:98–132. doi: 10.1210/er.2009-0009.
    1. Fabbri A, Jannini EA, Gnessi L, Ulisse S, Moretti C, Isidori A. Neuroendocrine control of male reproductive function. The opioid system as a model of control at multiple sites. J Steroid Biochem. 1989;32:145–150. doi: 10.1016/0022-4731(89)90155-6.
    1. Ceccarelli I, Rossi A, Maddalena M, Weber E, Aloisi AM. Effects of morphine on testosterone levels in rat C6 glioma cells: modulation by anastrozole. J Cell Physiol. 2009;221:1–4. doi: 10.1002/jcp.21830.
    1. Aloisi AM, Ceccarelli I, Fiorenzani P, Maddalena M, Rossi A, Tomei V, Sorda G, Danielli B, Rovini M, Cappelli A, Anzini M, Giordano A. Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats. Mol Pain. 2010;6:69. doi: 10.1186/1744-8069-6-69.
    1. Aloisi AM, Buonocore M, Merlo L, Galandra C, Sotgiu A, Bacchella L, Ungaretti M, Demartini L, Bonezzi C. Chronic pain therapy and hypothalamic-pituitary-adrenal axis impairment. PNEC. 2011. in press .

Source: PubMed

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