Tuesday, 22nd July 2014

Heroin Opiates

Opiates & Sexual Function

 

The relationship between opiate drug use and sexual activity is a complex mix of pharmacological and socioeconomic factors.  The high cost of maintaining a habit leads both women and men into prostitition as an alternative acquisitive crime.

A Canadian study[i] found 50% of female intravenous opiate users to be sex-trade workers, in the US the figures were 51-70% for women, and around 10% for men[ii], with a high incidence of high HIV-risk behaviour[iii].  Klee, studying heroin and amphetamine injecting women[iv], found “Marked differences were observed in sexual behaviour, amphetamine injectors reporting greater interest in sex and greater frequency of intercourse....  Over 80% in both groups had engaged in unprotected sex in the 6 months prior to interview.

 

Opiates have a long history as drugs which dull the sexual urge.  In the past 20 years the effect of opiates have been studied extensively in laboratory and farm animals.  There have been few studies in humans, mostly those involving patients receiving oral or spinal pain therapy, with little in the way of systematic controlled experiments.

 

For the purpose of this review, a computerised search of the scientific literature via the Medline database was conducted, using they keywords: morphine, naloxone, naltrexone, sexual, libido and rape, quotations (in italics) are taken from the abstracts of scientific papers reviewed.

 

Opiates

 

Opiate drugs are used clinically to treat pain, the best known examples being codeine, morphine and heroin (diamorphine).  These are all opiate-receptor agonists - i.e. they stimulate the firing of opiate receptors to produce the effects on mood and behaviour.  Opiate antagonists (naloxone or naltrexone) block the action of morphine and other agonists, reversing the effects of opiate overdose, analgesia or intoxication.

 

The body produces its own substances which act like opiate drugs, known as endorphins or endogenous opiates.  These act directly on the receptors, and can include both agonists (e.g. beta-endorphin) and antagonists.

 

Animal Studies

 

Rats and Mice: In male rats, morphine significantly reduces testosterone secretion[v], and “acts ... to impair noncontact erections and copulation.[vi] Tanko et al[vii] reported “morphine inhibited copulation” in both male and female rats.  Gessa et al[viii] found “naloxone induce copulatory behavior in sexually inactive male rats

 

Marin-Bivens & Olster[ix] found “naltrexone administration enhanced both sexual receptivity and proceptivity” in female rats, “naltrexone injection increased the display of sexual receptivity (lordosis quotient p < 0.05) and also elicited proceptivity (PRO), which was never observed after saline injection (p < 0.01).”  and that “Morphine treatment blocked these effects of naltrexone on sexual behaviors”.

 

In female rats, Vathy et al[x] reported: “naloxone infusion into the ventromedial hypothalamus 20 min before behavior testing reduced the inhibitory effects of systemically administered morphine on lordosis.”  Cicero et al reported: “morphine exposure during adolescence led to a pronounced inhibition of a number of indices of sexual maturation (e.g., serum testosterone and luteinizing hormone levels and reduced weights of the testes and seminal vesicles).”

 

In male rats, Band & Hull[xi] reported: “Morphine injections (to medial preoptic area and nucleus accumbens) reduced both the latency to ejaculate and the number of intromissions triggering ejaculation,... produced a failure to resume copulating following the second ejaculation,...shortened the latency to the first intromission and lengthened the second postejaculatory interval. Naloxone reversed the effects of morphine on intromission latency and attenuated the lowering of ejaculatory threshold.”  By contrast, Mitchell & Stewart[xii] found with ventral tegmental injections “morphine... increased, in a dose-orderly manner, the number of males that mounted, and the display of female-directed behavior.”, and also[xiii] that “males displayed more frequent female-directed behavior, such as pursuit of the female, anogenital exploration, and partial mounts”  Leyton & Stewart[xiv] found “the stimulation of central kappa opioid receptors inhibits sexual behavior in the male rat”   Gomez-Marrero et al[xv] found morphine to decrease erection and ejaculation frequency, and naloxone to reverse this effect.  Meyerson et al[xvi] found “In the female (rat), neonatal naltrexone treatment enhanced copulatory (lordosis response) and exploratory behavior.”  Agmo[xvii] found naloxone alone did not affect copulatory behaviour of male rats, whereas morphine “reduced the proportion of animals displaying sexual behavior” with “a dose-dependent reduction of mount, intromission and ejaculation percentages

 

Meyerson et al[xviii] reported: “Female rats treated neonatally with naltrexone displayed enhanced copulatory behaviour as adults, and the morphine-induced lordosis inhibitory effect was diminished.”  In male rats, Meyerson[xix] also found “beta-endorphin or morphine decreased exploratory activity and socio-sexual approaches.”  Lieblich et al[xx] found “naloxone... significantly reduced ejaculation and mounting in male rats in the weeks following castration. A similar effect was obtained by injecting morphine . In contrast, the same dosages of naloxone or morphine did not affect the sexual performance of gonadally intact males.”  The sex differences in response were outlined by Vathy[xxi], who concluded “prenatal morphine treatment... disrupts the development of reproductive function in females but has only minor effects on male reproductive function.”  Wiesenfield[xxii] found “intrathecal injection of morphine into female ovariectomized rats pretreated with oestradiol benzoate and progesterone inhibits sexual receptivity while injection of the opiate receptor antagonist naloxone enhances it. Similarly, intrathecal injection of morphine increases while injection of naloxone decreases the number of intromissions before ejaculation in male rat.”  Misra[xxiii], testing naloxone implants in male rats, found these to produce a side effect of “enhanced sexual activity (e.g., spontaneous penile erections)

 

McIntosh et al[xxiv] found naloxone to decrease sexual activity in sexually experienced rats, but increase it in sexually naive rats, whereas morphine completely abolished copulatory activity.  Sachs et al[xxv], studying penile reflexes and copulatory behaviour in male rats reported “Naloxone resulted in a small but reliable decrease in the number of penile flips (and) significantly prolonged the postejaculatory refractory period”   Saito et al[xxvi] concluded “opiate antagonists play a role in the regulation of lordosis behavior, but not proceptive behavior in female rats.”  Meijs-Roelofs[xxvii] found Naltrexone “advanced first ovulation in about 55%-75% of (juvenile female) rats”.  Wu and Noble[xxviii] concluded “opiate antagonists alter male copulatory behavior by enhancing the impact of stimuli occurring during the sexual interaction.”, whereas Mandenoff et al[xxix] found “Naltrexone provoked an increase in the (frequency) of ejaculations”  Allen et al[xxx] found that in female rats, naltrexone “facilitated sexual receptivity”.  Myers & Baum[xxxi] found naloxone and naltrexone to facilitate sexual performance in male rats, but Lieblich et al found “Naloxone... impaired sexual performance in castrated male rats, and in gonadally intact rats maintained on sweet solutions.

 

In female rats, Hulse et al[xxxii] reported “injection of naloxone resulted in marked elevations in serum FSH and LH, induced ovulation and increased the frequency of lordosis behaviour.”, and Sirinathsinghji[xxxiii] reported “the facilitation of lordosis behaviour induced by treatment with naloxone... may be due to enhanced Gonadotrophin releasing hormone release”, and that[xxxiv]beta-Endorphin regulates lordosis in female rats by modulating LH-RH release.”  In male mice, Landauer et al[xxxv] found “naloxone reversed the decrease in female investigation time observed with... morphine... an animal model can be used to study the disruption of socio-sexual behavior produced by opiates.”  Schechtman et al[xxxvi] concluded “mating is a biological stimulus for the release of endogenous opoids, possibly to (a) prevent intense sexual stimulation from becoming aversive, and (b) increase its reward value.

 

Van Furth[xxxvii] found naloxone to reduce the effect of smell on anticipatory sexual behaviour in male rats, whereas deCatanazaro[xxxviii], studying male mice suggested “the influences of prior social condition on male sexual activity are robust in the face of naloxone administration.” In male rats, Pfaus & Wilkins[xxxix] found “Naloxone... facilitated the display of mounts and intromissions”, Clark & Smith[xl] reported “naloxone ... evinced a facilitation of ejaculatory behavior”, Hughes et al[xli] reported naloxone “markedly facilitated copulatory responses

 

Rodriguez-Manzo et al[xlii] reported both naloxone and naltrexone to “exert a dose-based biphasic effect on the proportion of sexually exhausted rats displaying copulation.”, higher doses “facilitated copulation reflected as a shortening of the ejaculation latency and the interintromission interval and an increase in the copulatory rate” and “decreased the spontaneous ambulatory behaviour of sexually satiated rats without impairing sexual behaviour execution.”  The differences in behavioural effects of opiates, endorphins and antagonists[xliii] are attributed by Torii et al[xliv] to the time of administration in relation to steroid hormone secretion, concluding[xlv]opioidergic systems modulate an initial phase of estrogen action to induce lordosis and play a part in neural input from the forebrain structures to regulate female sexual receptivity.

 

Forsberg et al[xlvi] found naloxone to induce sexual receptivity in female rats immediately following coitus, and also during lactation[xlvii].  Lindblom et al[xlviii] found there to be differences in the effect of naloxone on already receptive or partially receptive female rats, having little effect in the former but ‘facilitated sexual behavior’ in the latter, finding the site of injection also to cause differences in response.  Wiesner & Moss[xlix]found beta-endorphin to suppress “Receptive behavior (lordosis) and proceptive behaviors (presentation and ear wiggling)... the mu-1 antagonist naloxazone... reversed the effects of beta-END on all behaviors tested.

 

Other Rodents:  In guinea-pigs, Olster[l] found that naloxone injections to the medial preoptic area/anterior hypothalamus reliably elicited female sexual display (lordosis - 87% positive response vs 12% for saline), and found[li] naloxone to produce a dose-related increase in lordosis behaviour, noting “the facilitatory effect of naloxone on sexual receptivity was completely blocked by concomitant injection of morphine”.

 

In male rabbits, Agmo et al[lii] found “Morphine was found to inhibit sex behavior in a dose dependent way. ... Naloxone also inhibited sexual behavior.” but added “The effects of morphine were reduced but not completely antagonized by several doses of naloxone”  Agmo also concluded[liii]peripheral opioid receptors are responsible for at least some of the inhibitory actions of morphine on male sexual behavior.”, and that[liv]Perhaps compulsive sexual activity obeys the same mechanisms as compulsive drug use in opiate addicts.

 

In hamsters, Ostrowski et al[lv] found “administration of morphine to female hamsters reliably decreases lateral displacement, a sensitive index of female sexual responsitivity... Large doses of naltrexone produced no reliable effects on sexual behavior during estrus in unmated females, nor did it attenuate the mating-induced decreases in sexual responding, regardless of the time of day of mating.”  They also found[lvi]Large doses of morphine consistently produced sedation and behavioral depression of responses to nociceptive stimuli. Smaller doses of morphine suppressed a measure of female sexual responding. The suppressive effects on sexual behavior were reversed by naloxone.” although there was no effect of naloxone alone in opioid-naive animals.  Murphy[lvii] reported “The debilitating effect of methadone was judged to be highly selective for sexual behavior since, for example, at 16 mg/kg of methadone, sexual behavior was eliminated but ambulatory activity was unaffected. Pretreatment with naltrexone blocked the effects of methadone and posttreatment reversed the effects, thereby indicating that the methadone was inhibiting sexual behavior by acting on specific opiate receptors.” Donham et al[lviii] found naloxone to advance puberty in female hamsters by enhancing LH release.

 

Farm Animals In rams[lix], morphine decreased ejuaculation frequency, whereas naloxone increased courship behaviour and ejaculatron frequency in sexually active animals, and in female sheep[lx] naloxone increased the frequency of pulse-secretion of luteinising (sex) hormone, and was involved in the onset of oestrus, Fuentes[lxi] reporting “naloxone facilitates the expression of oestrus in the ewe during anoestrus and lactation.”, and in male goats[lxii].”naloxone enhances libido... during anoestrus

 

Non-Human Primates:  Studying rhesus monkeys, Abbott et al[lxiii] reported “The proportion of approaches of the female to the male was increased when naloxone, but not naltrexone, was given.”  In male Talapoin monkeys, Meller et al[lxiv] reported “Naltrexone significantly reduced sexual behaviour in previously active males”, whereas Martensz et al[lxv] found differences in response depending on the monkeys level in the social hierarchy, concluding “Altered opiate neural activity may be responsible for the depressed levels of sexual behaviour and gonadal function observed in monkeys at the bottom of the hierarchy.”  In male rhesus monkeys, Gilbeau & Smith[lxvi] found naloxone to reverse stress-related reproductive effects including resoration of LH secretion to pre-stress levels, however Glick et al[lxvii] found that “Despite the positive behavioral cues of the females, the males failed to initiate heterosexual interactions at any level of naloxone therapy.

 

Non-mammalian vertebrates:  The influence of endogenous opiates on sexual behaviour appears relatively early in vertebrate evolution, in newts[lxviii], “bremazocine, a kappa-receptor opiate agonist, can markedly reduce sexual activity and that an ip injection of naloxone can reverse this inhibition in a dose-dependent fashion.”, effects on sex hormones and/or sexual behaviour have also been demonstrated in lizards[lxix], and birds[lxx], where “compared to controls a greater number of naloxone-treated birds copulated in the test arena on the first day” and[lxxi]Naloxone treatment showed a significant increase in the frequency of several aggressive actions and the effect was dose dependent.

 

Human Studies

 

In studies of pain-management patients receiving opioid analgesic therapy, Abs et al[lxxii] reported: “Decreased libido or impotency was present in 23 of 24 men..., (and) in 22 of 32 women receiving opioids.”  Paice et al[lxxiii] found that in male patients receiving spinal opiate analgesics: “All patients had some reduction in libido and four patients had difficulty obtaining or maintaining an erection.

 

Ferrari F, Baggio G[lxxiv] found naloxone “markedly potentiated the stimulant effect” (of a dopamine agonist aphrodisiac) “characterized by recurrent episodes of penile erection” and concluded “The combination of dopamine receptor stimulants with naloxone might offer a new possibility for erection defect therapy.”  Del Bene et al[lxxv] concluded that sexual arousal may be included among the crises of morphine abstinence.  Frajese et al[lxxvi] suggested naloxone therapy as an option in the treatment of impotence and sexual dysfunction due to stress-related conditions.  However in a pilot study of naloxone treatment for sexually unresponsive women, Brady et al[lxxvii] found it failed to increase sexual arousal.  In men, Murphy et al[lxxviii] found naloxone blocked oxytocin release during orgasm, and also noted “ a decrease in the level of subjective arousal and pleasure at orgasm”

 

Sheridan[lxxix] stated “Many heroin addicts and addicts on methadone treatment exhibit sexual dysfunction.”  Smith et al[lxxx] found “in women chronically abusing high doses of heroin, one may not only see a reduction of sexual desire and performance, but also irregular menstrual cycles, and occasionally, amenorrhea, as a result of the depressive effects of the opiate on pituitary hormones.”  Mirin et al[lxxxi] reported “Although opiate addicts often equate the drug experience with sexual orgasm, diminished libido and impaired sexual performance are common sequelae of chronic use. Early clinical studies suggested that opiates may interfere with sex hormone secretion.

 

van Ahlen et al[lxxxii] found “early-morning erections increased significantly under naltrexone therapy”  In a further trial for males with erectile dysfunction, Brennemann et al[lxxxiii] concluded “treatment with naltrexone significantly raises the rate of spontaneous early morning erections when compared to controls.”  Fabbri et al[lxxxiv] found “naltrexone therapy significantly increased the number of successful coitus compared to placebo... All the patients experienced a significant increase in morning and spontaneous full penile erections/week.”  Sandyk[lxxxv] found naltrexone to suppress abnormal sexual behaviour in Tourettes syndrome patients.  However Goldstein et al[lxxxvi] using a single male subject, found naloxone to have “no effect on sexual arousal, penile erection, ejaculation, or orgasm”.  In chronic pain patients receiving opiate therapy, Finch et al[lxxxvii] found “Men and both premenopausal and postmenopausal women had evidence of hypogonadism”, and Paice et al[lxxxviii] cited ‘loss of libido’ as a common side effect of such therapy, concluding[lxxxix]Patients should be queried regarding sexual function and should be cautioned regarding the possibility of these adverse effects prior to initiating spinal opioids. Supplemental testosterone should be considered to treat this dysfunction.

 

In a study of luteinising hormone (LH) secretion during different phases of the menstrual cycle, Genazzani et al[xc] reported “In fertile women, naloxone administration increases LH levels in the luteal phase but not in the follicular phase. In the postmenopausal period, naloxone has no effect on LH release; estrogen/progestin therapy does restore the LH response.”  Bernasconi et al[xci] found the LH naloxone response in healthy adolescent girls to be restricted to the “preovulatory and luteal phases”.  Following a study of endocrine function in adolescent boys with delayed sexual development, Veldhuis et al[xcii] concluded “maturation of the opiate-related neuroendocrine system occurs during the course of sexual development in the human.

 

Summary - Opiates and sexual function

 

Opiates are clearly involved at a very basic level of sexual function, from early in the evolutionary chain, with effects on endocrine (hormone) function found in human and animal studies.

 

Most animal studies have found opiate agonists, such as endogenous opiates or morphine, to reduce sexual receptivity, and antagonists such naloxone or naltrexone to increase female receptivity to sexual stimuli.  Some studies in rats have even suggested that active (proceptive) seeking of sexual activity can be induced by opiate antagonists.  Other studies have investigated the basis of these effects in detail, proposing a receptor-mediated relationship between endogenous opiates and sex-hormone secretion, and differences in the nature and degree of effects on sexual arousal at different stages of the oestrus (menstrual) cycle.

 

In human subjects opiate therapy or abuse is widely associated with loss of libido (sex drive), however the few studies of the effect of naloxone or naltrexone have been inconclusive, some suggesting a role in the treatment of impotence in males, although the lone study of naloxone on a small number of sexually unresponsive women found no effect on sexual arousal.  Given the documented effects on libido of opiate agonists, a rebound effect of enhanced sexual arousal during abstinence or upon administration of opiate antagonists would normally be expected.

 

Any drug effect on receptiveness in human females must be viewed in the context of psychological, environmental and cognitive factors.  It is one factor to be considered among many, when assessing the state of mind of an individual.  On balance, however, administration of naltrexone to a female ex-heroin addict is more likely to increase the likelihood of consensual sexual activity, or appearance of consent to such activity through body language or behaviour, than to reduce it.

 


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