Oxycondone
Bluelighter
- Joined
- Jan 20, 2011
- Messages
- 424
Hey Everyone,
I know this isn't an Aussie only phenomena I just wanted to highlight the fact that chronic opiates usage has significant detrimental effects on testosterone levels, which can be very problematic especially for men.
*edit* snip
Here's a 2006 paper detailing the phenomenon in detail for any who are interested:
Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats
I. Ceccarelli, A.M. De Padova, P. Fiorenzani, C. Massafra and A.M. Aloisi,
Discussion
The main result of the present study is the demonstration that in male rats a single administration of opioids changes plasma and/or brain sex hormone levels depending on the dose and the time after treatment. Opioids are among the most useful and promising substances for pharmacological pain therapy. However, the multifaceted aspects of one of their side effects, hypogonadism, have not been adequately investigated. In the present experiment, sex hormones were determined 4 and 24 h after a single s.c. administration of four opioids commonly used for the treatment of moderate to severe pain, with the aim of evaluating the differences among them in male rats.
The opioids chosen for this experiment, morphine, tramadol, fentanyl and buprenorphine, all induce analgesia but are known to have different mechanisms of action and time-courses. Morphine acts on all opioid receptors, albeit with different affinity (Gourlay, 2005). Tramadol is a μ-opioid receptor agonist but also interferes with serotonin and norepinephrine uptake (Raffa et al., 1993). Fentanyl is a μ-opioid receptor agonist, is very lipophilic and passes the blood–brain barrier very rapidly, as shown by its rapid onset and short duration of action (Megens et al., 1998). Buprenorphine is a partial μ-opioid receptor agonist and a partial antagonist of the κ- and δ-opioid receptors (see Johnson et al., 2005). These important differences in mechanism of action are reflected in the testosterone changes. A single injection of these opioids induced roughly the same effect on plasma testosterone levels at 4 h after treatment, when testosterone was drastically reduced in animals treated with the high concentrations. In the same animals, brain testosterone levels were much lower than control for morphine, fentanyl and tramadol, while there was no significant difference from control for buprenorphine. Treatment with the low concentration of the same substances induced very low levels of plasma testosterone at 4 h in all groups except tramadol 10 mg/kg. No data are available for the effects of the low opioid concentrations in the brain.
Although transitory, the decreases in testosterone plasma levels recorded in this experiment are compatible with the condition called hypogonadism.
Unlike the blood samples taken 4 h after treatment, those collected 24 h after treatment from groups treated with the low opioid concentrations had testosterone levels even three times higher than control, whereas testosterone did not differ from control in all groups treated with the high concentrations. Similarly, the brain testosterone levels did not differ from control in animals treated with the high opioid concentrations.
Before trying to explain these results, it is best to discuss the plasma estradiol levels determined in the same groups at both 4 and 24 h. In groups killed 4 h after treatment, the plasma estradiol levels were more sensitive to the concentration of the opioids than testosterone. For tramadol, morphine and buprenorphine, estradiol was lower than control only in the low dose groups, while the high dose groups did not differ from control. Interestingly, in the fentanyl group, plasma estradiol levels did not differ from control with either concentration. To analyze this dose-dependent reduction, we must also consider the E/T ratio, as estradiol is mostly obtained by aromatization of testosterone (Simpson 2003 and Simpson 2004; Patchev et al., 2004). This ratio remained at control levels only in the animals treated with the low concentrations of morphine, tramadol and buprenorphine, while the E/T values were always higher than control in the high dose groups.
Plasma testosterone is the main factor affecting plasma estradiol concentration. Much of the physiology of androgens can be explained by the concept that testosterone functions as a circulating pro-hormone that is converted in target tissues, on the one hand to 5α-dihydrotestosterone (DHT) and on the other hand to estradiol (see Aloisi and Bonifazi, 2006). The transformation of testosterone into estradiol is due to the enzyme aromatase. The regulation of this enzyme is highly complex, being influenced by both the substrate and products as well as by non-steroidal regulators, including catecholamines (Simpson, 2003). Aromatase protein and its activity have been detected in brain tissues of all mammalian species studied thus far. In rats, its activity is expressed in neurons of discrete hypothalamic, preoptic, limbic, hippocampal, neocortical and midbrain regions. The protein and its activity vary greatly through the stages of life. Many studies have focused on the possible dependence of aromatase on androgens (Simpson, 2004).
Therefore, one of the most probable hypotheses to explain the present findings is that, immediately after treatment, low opioid concentrations induce a reduction in synthesis (low testosterone, low estradiol) while high concentrations lead to an increase in aromatization (low testosterone, high estradiol), i.e. in addition to decreasing testosterone production, morphine, tramadol and buprenorphine (high dose) would also increase aromatization of testosterone to estradiol. In the fentanyl groups, the plasma estradiol levels did not differ from control with either dose, but the E/T ratio was much higher than control in both the low and high dose groups. Thus, we can hypothesize that testosterone was decreased in fentanyl-treated animals, either because it was not produced or it was reduced to DHT via the 5-α reductase pathway.
In animals killed at 24 h, all groups treated with the low opioid concentrations had higher testosterone levels than control, whereas the estradiol levels were very low with respect to control suggesting a kind of rebound effect of the hypothalamus–pituitary–gonadal axis. This result can also be interpreted as a change in aromatase activity: it seems that the decrease and then disappearance of the opioid from the circulation induced blockage of the enzyme that transforms testosterone into estradiol. This is confirmed by the very low E/T values in these groups.
Another interesting result of the present study is the lack of significant changes in plasma testosterone at 4 h after treatment with tramadol 10 mg/kg (the low concentration) and the increase in plasma testosterone and decrease in plasma estradiol at 24 h after treatment. Although the mechanism of action of tramadol is similar to that of morphine, due to the interaction with the μ-opioid receptor, it produces less severe gastrointestinal and cardiovascular side-effects and lower respiratory depression and dependence than morphine (Meert and Vermeirsch, 2005).
The important neural systems affected by this opioid, i.e. the serotoninergic and noradrenergic pathways, suggest that rather than there being a lack of effect of the low tramadol dose, this concentration induces effects without changing the hypothalamus–pituitary–gonadal axis. Indeed, it has been shown that this concentration can induce strong behavioral effects (see Rojas-Corrales et al., 2002) but contradictory analgesic effects depending on the route of administration and the nociceptive test used. Moreover, this concentration has been found to affect immune parameters (Tsai and Won 2001 and Sacerdote et al 1997).
Due to the important role played by testosterone and its metabolites in the CNS (Hammond et al 2001, Vadakkadath Meethal and Atwood 2005 and Patchev et al 2004), we set up the method to evaluate if the modifications induced by opioids in the blood were paralleled by central modifications. The results confirm the presence of a neural pool of testosterone in the brain and indicate the ability of opioids to change it. Testosterone synthesis in the brain has been described in hippocampal neurons (Hojo et al., 2004); indeed, these neurons appear to contain a set of enzymes that catalyze the synthesis of testosterone from cholesterol. Moreover, the presence of aromatase confirms the further transformation of this hormone into estradiol, as recently shown by a study reporting that cultured hippocampal neurons release estradiol into the medium (Prange-Kiel et al., 2003). Although technical problems did not allow us to determine the levels of estradiol and/or other hormones in brain tissue of the animals studied in this experiment, our results indicate a strong effect of the opioids (except buprenorphine) on brain testosterone levels. In particular, the very low levels at 4 h after treatment and the return to control levels at 24 h suggest a rapid and short-lasting rearrangement of the system in response to opioid treatment.
In the present study, the demonstration that there are opioids that do not affect central levels of testosterone and, presumably of estradiol, is particularly important. Although we are unable at present to explain why the action of buprenorphine in the brain is dissociated from its effect on circulating levels of testosterone, the fact that buprenorphine can be used as an opioid substitute to rescue addicts without inducing hypogonadism (Bliesener et al., 2005) suggests that this type of compound is most suitable for prolonged use. However, further detailed studies are required to better evaluate the long-term effects of treatment. Regarding the testosterone plasma levels in the buprenorphine-treated groups, the available data suggest that the drop in plasma testosterone levels could be due to a transitory effect of the drug, probably mediated by μ-opioid receptor activation in a hypothalamic area. The increase of binding with other opioid receptors would have counteracted this action, maintaining control levels of testosterone in the brain. Indeed, numerous literature reports indicate a dose-dependent effect of buprenorphine due to its agonistic action on μ-opioid receptors but antagonistic action on other opioid receptors (Johnson et al., 2005). Hence, we cannot exclude that the time needed to reach its maximum levels would be sufficient to cause the gonadotropin inhibition responsible for the decrease in testosterone. In fact, it has been suggested that buprenorphine at low doses (i.e. 0.003–0.03 mg/kg) acts at one receptor site to induce an effect, whereas at higher doses (0.1–0.3 mg/kg) it may interact with a second site of lower affinity to inhibit the same effect (Amoroso et al 1988 and Meert and Vermeirsch 2005).
The fact that buprenorphine behaves differently from the other opioids in modulating the CNS is not new since it was previously shown to differ from morphine and other opioids. Indeed, the initial binding is relatively slow compared with opioids such as fentanyl, even though the onset of analgesia is not dissimilar, and then it takes a long time to come off the receptor (Meert and Vermeirsch, 2005). Moreover, buprenorphine does not induce internalization of opioid receptors (Zaki et al., 2000), and while PAG administration of buprenorphine significantly suppresses plasma ACTH levels at 40–140 min after treatment, morphine increases plasma ACTH levels at 20–160 min after treatment (Gomez-Flores and Weber, 2000).
Conclusion
The side effects of opioids are numerous and may interfere with their important analgesic action. Nausea, respiratory depression, vomiting, constipation and itching are well known by clinicians, although they are commonly accepted because of the high efficacy of these analgesics. Hypogonadism is also a ‘normal’ side effect in patients treated with opioids, as we recently described in patients suffering chronic pain and chronically treated with i.t. morphine (Aloisi et al., 2005). Yet, this condition is rarely taken into account by clinicians.
Men with low endogenous androgen levels due to ageing or hypogonadism report more anxiety symptoms and decreased mood than their androgen-replaced counterparts (Craft et al 2004 and Seftel 2005). Moreover, in male rats, gonadectomy was found to decrease the potency of morphine, while chronic testosterone treatment restored the potency to that recorded in sham-gonadectomized animals (Stoffel et al., 2003). We have recently shown that supraphysiological levels of testosterone reduce formalin-induced pain responses in female rats and that physiological levels of testosterone in male rats reduce the behavioral and neuronal responses induced by a repeated-formalin test (Ceccarelli et al 2003 and Aloisi et al 2004). Therefore, it is important that testosterone be kept at physiological levels to avoid hypogonadism, i.e. the lack of a hormone known to have analgesic effects and also to be involved in neuroprotection and many other functions which if maintained can improve the quality of life of patients.
Mods feel free to move this if you feel the need. Hopefully this information will help people and get those affected to seek treatment.
Cheers,
Oxy
I know this isn't an Aussie only phenomena I just wanted to highlight the fact that chronic opiates usage has significant detrimental effects on testosterone levels, which can be very problematic especially for men.
*edit* snip
Here's a 2006 paper detailing the phenomenon in detail for any who are interested:
NSFW:
Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats
I. Ceccarelli, A.M. De Padova, P. Fiorenzani, C. Massafra and A.M. Aloisi,
Discussion
The main result of the present study is the demonstration that in male rats a single administration of opioids changes plasma and/or brain sex hormone levels depending on the dose and the time after treatment. Opioids are among the most useful and promising substances for pharmacological pain therapy. However, the multifaceted aspects of one of their side effects, hypogonadism, have not been adequately investigated. In the present experiment, sex hormones were determined 4 and 24 h after a single s.c. administration of four opioids commonly used for the treatment of moderate to severe pain, with the aim of evaluating the differences among them in male rats.
The opioids chosen for this experiment, morphine, tramadol, fentanyl and buprenorphine, all induce analgesia but are known to have different mechanisms of action and time-courses. Morphine acts on all opioid receptors, albeit with different affinity (Gourlay, 2005). Tramadol is a μ-opioid receptor agonist but also interferes with serotonin and norepinephrine uptake (Raffa et al., 1993). Fentanyl is a μ-opioid receptor agonist, is very lipophilic and passes the blood–brain barrier very rapidly, as shown by its rapid onset and short duration of action (Megens et al., 1998). Buprenorphine is a partial μ-opioid receptor agonist and a partial antagonist of the κ- and δ-opioid receptors (see Johnson et al., 2005). These important differences in mechanism of action are reflected in the testosterone changes. A single injection of these opioids induced roughly the same effect on plasma testosterone levels at 4 h after treatment, when testosterone was drastically reduced in animals treated with the high concentrations. In the same animals, brain testosterone levels were much lower than control for morphine, fentanyl and tramadol, while there was no significant difference from control for buprenorphine. Treatment with the low concentration of the same substances induced very low levels of plasma testosterone at 4 h in all groups except tramadol 10 mg/kg. No data are available for the effects of the low opioid concentrations in the brain.
Although transitory, the decreases in testosterone plasma levels recorded in this experiment are compatible with the condition called hypogonadism.
Unlike the blood samples taken 4 h after treatment, those collected 24 h after treatment from groups treated with the low opioid concentrations had testosterone levels even three times higher than control, whereas testosterone did not differ from control in all groups treated with the high concentrations. Similarly, the brain testosterone levels did not differ from control in animals treated with the high opioid concentrations.
Before trying to explain these results, it is best to discuss the plasma estradiol levels determined in the same groups at both 4 and 24 h. In groups killed 4 h after treatment, the plasma estradiol levels were more sensitive to the concentration of the opioids than testosterone. For tramadol, morphine and buprenorphine, estradiol was lower than control only in the low dose groups, while the high dose groups did not differ from control. Interestingly, in the fentanyl group, plasma estradiol levels did not differ from control with either concentration. To analyze this dose-dependent reduction, we must also consider the E/T ratio, as estradiol is mostly obtained by aromatization of testosterone (Simpson 2003 and Simpson 2004; Patchev et al., 2004). This ratio remained at control levels only in the animals treated with the low concentrations of morphine, tramadol and buprenorphine, while the E/T values were always higher than control in the high dose groups.
Plasma testosterone is the main factor affecting plasma estradiol concentration. Much of the physiology of androgens can be explained by the concept that testosterone functions as a circulating pro-hormone that is converted in target tissues, on the one hand to 5α-dihydrotestosterone (DHT) and on the other hand to estradiol (see Aloisi and Bonifazi, 2006). The transformation of testosterone into estradiol is due to the enzyme aromatase. The regulation of this enzyme is highly complex, being influenced by both the substrate and products as well as by non-steroidal regulators, including catecholamines (Simpson, 2003). Aromatase protein and its activity have been detected in brain tissues of all mammalian species studied thus far. In rats, its activity is expressed in neurons of discrete hypothalamic, preoptic, limbic, hippocampal, neocortical and midbrain regions. The protein and its activity vary greatly through the stages of life. Many studies have focused on the possible dependence of aromatase on androgens (Simpson, 2004).
Therefore, one of the most probable hypotheses to explain the present findings is that, immediately after treatment, low opioid concentrations induce a reduction in synthesis (low testosterone, low estradiol) while high concentrations lead to an increase in aromatization (low testosterone, high estradiol), i.e. in addition to decreasing testosterone production, morphine, tramadol and buprenorphine (high dose) would also increase aromatization of testosterone to estradiol. In the fentanyl groups, the plasma estradiol levels did not differ from control with either dose, but the E/T ratio was much higher than control in both the low and high dose groups. Thus, we can hypothesize that testosterone was decreased in fentanyl-treated animals, either because it was not produced or it was reduced to DHT via the 5-α reductase pathway.
In animals killed at 24 h, all groups treated with the low opioid concentrations had higher testosterone levels than control, whereas the estradiol levels were very low with respect to control suggesting a kind of rebound effect of the hypothalamus–pituitary–gonadal axis. This result can also be interpreted as a change in aromatase activity: it seems that the decrease and then disappearance of the opioid from the circulation induced blockage of the enzyme that transforms testosterone into estradiol. This is confirmed by the very low E/T values in these groups.
Another interesting result of the present study is the lack of significant changes in plasma testosterone at 4 h after treatment with tramadol 10 mg/kg (the low concentration) and the increase in plasma testosterone and decrease in plasma estradiol at 24 h after treatment. Although the mechanism of action of tramadol is similar to that of morphine, due to the interaction with the μ-opioid receptor, it produces less severe gastrointestinal and cardiovascular side-effects and lower respiratory depression and dependence than morphine (Meert and Vermeirsch, 2005).
The important neural systems affected by this opioid, i.e. the serotoninergic and noradrenergic pathways, suggest that rather than there being a lack of effect of the low tramadol dose, this concentration induces effects without changing the hypothalamus–pituitary–gonadal axis. Indeed, it has been shown that this concentration can induce strong behavioral effects (see Rojas-Corrales et al., 2002) but contradictory analgesic effects depending on the route of administration and the nociceptive test used. Moreover, this concentration has been found to affect immune parameters (Tsai and Won 2001 and Sacerdote et al 1997).
Due to the important role played by testosterone and its metabolites in the CNS (Hammond et al 2001, Vadakkadath Meethal and Atwood 2005 and Patchev et al 2004), we set up the method to evaluate if the modifications induced by opioids in the blood were paralleled by central modifications. The results confirm the presence of a neural pool of testosterone in the brain and indicate the ability of opioids to change it. Testosterone synthesis in the brain has been described in hippocampal neurons (Hojo et al., 2004); indeed, these neurons appear to contain a set of enzymes that catalyze the synthesis of testosterone from cholesterol. Moreover, the presence of aromatase confirms the further transformation of this hormone into estradiol, as recently shown by a study reporting that cultured hippocampal neurons release estradiol into the medium (Prange-Kiel et al., 2003). Although technical problems did not allow us to determine the levels of estradiol and/or other hormones in brain tissue of the animals studied in this experiment, our results indicate a strong effect of the opioids (except buprenorphine) on brain testosterone levels. In particular, the very low levels at 4 h after treatment and the return to control levels at 24 h suggest a rapid and short-lasting rearrangement of the system in response to opioid treatment.
In the present study, the demonstration that there are opioids that do not affect central levels of testosterone and, presumably of estradiol, is particularly important. Although we are unable at present to explain why the action of buprenorphine in the brain is dissociated from its effect on circulating levels of testosterone, the fact that buprenorphine can be used as an opioid substitute to rescue addicts without inducing hypogonadism (Bliesener et al., 2005) suggests that this type of compound is most suitable for prolonged use. However, further detailed studies are required to better evaluate the long-term effects of treatment. Regarding the testosterone plasma levels in the buprenorphine-treated groups, the available data suggest that the drop in plasma testosterone levels could be due to a transitory effect of the drug, probably mediated by μ-opioid receptor activation in a hypothalamic area. The increase of binding with other opioid receptors would have counteracted this action, maintaining control levels of testosterone in the brain. Indeed, numerous literature reports indicate a dose-dependent effect of buprenorphine due to its agonistic action on μ-opioid receptors but antagonistic action on other opioid receptors (Johnson et al., 2005). Hence, we cannot exclude that the time needed to reach its maximum levels would be sufficient to cause the gonadotropin inhibition responsible for the decrease in testosterone. In fact, it has been suggested that buprenorphine at low doses (i.e. 0.003–0.03 mg/kg) acts at one receptor site to induce an effect, whereas at higher doses (0.1–0.3 mg/kg) it may interact with a second site of lower affinity to inhibit the same effect (Amoroso et al 1988 and Meert and Vermeirsch 2005).
The fact that buprenorphine behaves differently from the other opioids in modulating the CNS is not new since it was previously shown to differ from morphine and other opioids. Indeed, the initial binding is relatively slow compared with opioids such as fentanyl, even though the onset of analgesia is not dissimilar, and then it takes a long time to come off the receptor (Meert and Vermeirsch, 2005). Moreover, buprenorphine does not induce internalization of opioid receptors (Zaki et al., 2000), and while PAG administration of buprenorphine significantly suppresses plasma ACTH levels at 40–140 min after treatment, morphine increases plasma ACTH levels at 20–160 min after treatment (Gomez-Flores and Weber, 2000).
Conclusion
The side effects of opioids are numerous and may interfere with their important analgesic action. Nausea, respiratory depression, vomiting, constipation and itching are well known by clinicians, although they are commonly accepted because of the high efficacy of these analgesics. Hypogonadism is also a ‘normal’ side effect in patients treated with opioids, as we recently described in patients suffering chronic pain and chronically treated with i.t. morphine (Aloisi et al., 2005). Yet, this condition is rarely taken into account by clinicians.
Men with low endogenous androgen levels due to ageing or hypogonadism report more anxiety symptoms and decreased mood than their androgen-replaced counterparts (Craft et al 2004 and Seftel 2005). Moreover, in male rats, gonadectomy was found to decrease the potency of morphine, while chronic testosterone treatment restored the potency to that recorded in sham-gonadectomized animals (Stoffel et al., 2003). We have recently shown that supraphysiological levels of testosterone reduce formalin-induced pain responses in female rats and that physiological levels of testosterone in male rats reduce the behavioral and neuronal responses induced by a repeated-formalin test (Ceccarelli et al 2003 and Aloisi et al 2004). Therefore, it is important that testosterone be kept at physiological levels to avoid hypogonadism, i.e. the lack of a hormone known to have analgesic effects and also to be involved in neuroprotection and many other functions which if maintained can improve the quality of life of patients.
Mods feel free to move this if you feel the need. Hopefully this information will help people and get those affected to seek treatment.
Cheers,
Oxy
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