Norman J. Uretsky, Ph.D. is a Professor of Pharmacology in the College of Pharmacy at The Ohio State University. Dr. Uretsky's research interests include neuropharmacology, neurotransmitter release in animal behavior and neurological diseases. If you have questions for Dr. Uretsky regarding medications, please send those to Sandy Siegel; we will attempt to have your questions addressed in the next newsletter.

My doctor has me on a combination of Neurontin (gabapentin-300 mg three times a day) and mexiletine (Mexitil-150 mg three times a day). Can you discuss how this combination of drugs works to decrease the paresthesias. The combo seems to work better than a higher level of Neurontin alone, and without the brain fogginess that the Neurontin causes.

A paresthesia is a spontaneously occurring abnormal sensation, which sometimes can be painful. The sensation is usually caused by a type of neuropathy that produces an impairment in the function of sensory nerves in the periphery or spinal cord. The sensory nerves send spontaneous nerve impulses, which create the abnormal sensation. Paresthesias frequently respond poorly to standard pain therapies.

The therapeutic approach to neuropathic sensory complaints is to administer drugs to inhibit the elevated spontaneous activity of the neuron. There are a variety of drugs that will do this, including anticonvulsant drugs and antiarrhythmic drugs. Neurontin, which is widely used to treat neuropathic conditions, is classified as an anticonvulsant drug. At the present time, its mechanism of action is unclear. Some pharmacologists believe that the drug blocks calcium ion entry into nerve cells, which would inhibit the release of neurotransmitters within a sensory pathway. Other scientists believe that Neurontin enhances the effects of the inhibitory neurotransmitter, GABA. The drug has a wide dose range but at high doses, it produces among other effects, sedation, blurry vision, and dizziness. I assume these equate with brain fogginess.

Mexiletine (Mexitil) is an orally active analog of the local anesthetic, lidocaine (lidocaine is not orally active). Like lidocaine, it is used primarily as an antidysrhythmic drug to correct abnormal rhythms of the heart. Like lidocaine, mexiletine has also been shown to be effective in certain neuropathic conditions. Mexiletine and lidocaine produce their effects by blocking sodium channels of excitable tissue, like heart and nerve cells, preventing sodium ion from entering the tissue. Such an action would inhibit spontaneous overactivity in nerve cells without inhibiting normal nerve activity. The drug when taken orally does not produce a numbing sensation like that produced by the local administration of local anesthetic drugs. Mexiletine, like Neurontin, also has dose-limiting side effects.

Mexiletine and Neurontin have different mechanisms of action in inhibiting the spontaneous nerve impulses in nerve cells. Frequently two drugs that produce their effects by different mechanisms are used in combination because it is possible to achieve a greater therapeutic effect than that produced by each drug alone. The combination therapy may, therefore, allow lower doses of each drug to be used, thereby reducing the adverse effects produced by each drug.

What is the effect of the drug sildenafil (Viagra) in women? How does this drug produce its effects? Is there research going on regarding drugs that are designed to assist women who experience sexual dysfunction from neurological conditions?

Three Stages of the Sexual Response

In order to understand the effects of drugs on sexual function, it is useful to divide the sexual response into three stages. The first stage, libido, refers to the desire for sex or sex drive. Libido is influenced by sexually-related thoughts and sensations. It is also influenced by hormonal factors, such as levels of estrogenic and androgenic hormones. Current evidence suggests that androgenic hormones released from the primary sex organs (testes and ovaries) and the adrenal gland play a significant role in determining the intensity of sex drive. In addition, since libido is a drive for a type of pleasure or reward, it is in part mediated by dopamine transmission in the nucleus accumbens and other forebrain regions. Dopamine transmission at these sites is postulated to mediate the rewarding sensations associated with drugs of abuse, such as heroin, cocaine, and amphetamine. Finally, dopamine transmission in the hypothalamus also plays a role in the sex drive.

The second stage of the sexual response, which is referred to as arousal, is initiated by a subjective sense of sexual excitement, experienced as anticipation and desire. This feeling induces an increase in nerve impulses that travel from specific sites in the brain through the spinal cord to peripheral neurons. These neurons, which innervate blood vessels carrying blood to erectile tissue (penis, clitoris, etc.), synthesize and release nitric oxide, a gas, from their nerve terminals. The released nitric oxide diffuses into vascular smooth muscle and binds to and activates an enzyme, guanylate cyclase, which induces the formation of a compound called cyclic GMP. The newly formed cyclic GMP mediates the relaxation of vascular smooth muscle, resulting in dilation or opening of arteries that carry blood to erectile tissue. As a result, blood will flow into erectile tissue, producing tissue enlargement and swelling (men and women) and increasing mucus secretion (women), which is responsible for lubrication. The dilating action of cyclic GMP on blood vessels is terminated by its interaction with the enzyme, phosphodiesterase type-5, which metabolizes (chemically changes) cyclic GMP to an inactive metabolite. Thus, this enzyme, phosphodiesterase type-5, plays an important role in terminating the swelling of the erectile tissue by metabolizing cyclic GMP. It is worth noting that acetylcholine, a neurotransmitter released from parasympathetic nerves, also plays a role in erection. The acetylcholine is released from neurons and produces a constriction of veins. This serves to occlude the outflow of blood from erectile tissue, resulting in a further increase in pressure in blood vessels of erectile tissue, producing additional swelling.

The third stage of the sexual response is referred to as the orgasm or the climax of sexual pleasure. In the male, this stage involves ejaculation. In the female, it involves the contraction of various muscles throughout the body, as well as the rhythmical contraction of the muscles of the vagina and uterus, which is produced by spinal reflexes. The eventual removal of blood from erectile tissue is in part the result of the metabolism of the cyclic GMP by phosphodiesterase type-5 (as described above) and the activity of sympathetic nerves that innervate blood vessels. Norepinephrine released from sympathetic nerves activates alpha adrenergic receptors on the smooth muscle of arteries, producing muscle contraction which results in constriction or narrowing of the blood vessels. This would decrease the flow of blood to erectile tissue. In addition, released norepinephrine can activate beta adrenergic receptors on the smooth muscle of veins, and the resulting dilation of veins increases the flow of blood away from the erectile tissue.

Sildenafil (Viagra) Actions in Treating Male Sexual Dysfunction

It has been estimated that 20-30 million American men have difficulty or have been unable to achieve an erection that is sufficient for sexual intercourse. There are many possible causes of this condition. For example, a neurological impairment would interfere with the functioning of nerves carrying impulses from the brain to the peripheral neurons regulating the accumulation of blood in erectile tissue. In addition, certain drugs (for example, antidepressants that inhibit serotonin reuptake), as well as psychological problems, e.g., depression, may also interfere with the activity of neurons that regulate erectile tissue. Presumably in these circumstances, insufficient nitric oxide is released from neurons, resulting in an insufficient formation of cyclic GMP. As a consequence, the level and/or duration of cyclic-GMP in smooth muscle would be inadequate to produce or maintain sufficient dilation of the blood vessels of erectile tissue in response to sexual excitement. In males, this would be expressed as the inability to produce a penile erection. An inability to produce an erection could also be caused by performance anxiety. This anxiety activates the sympathetic nervous system (fight or flight reflex) causing the excessive release of norepinephrine from sympathetic nerve endings. The subsequent activation of alpha-adrenergic receptors produces a constriction rather than a dilation of the arteries of erectile tissue, thereby inhibiting blood flow and erection. Another mechanism to explain impaired erection is that the arteries supplying blood to erectile tissue may be partially blocked (by atherosclerotic plaques), preventing the increased blood flow into erectile tissue. In all of these conditions, the arousal phase of the sexual response in which sexual excitement leads to the swelling of erectile tissue would be impaired, and a higher concentration of cyclic GMP during the arousal stage might induce the dilation of erectile tissue arteries, when a lower concentration would be ineffective.

Sildenafil (Viagra) was introduced in 1998 to treat erectile dysfunction (impotence) in males, and the sales of this drug have been tremendous, reaching approximately $1 billion dollars with physicians writing 40,000 prescriptions a day. The drug is reported to reverse erectile dysfunction in a majority of men. The drug produces its therapeutic effects in this condition by enhancing the dilation of blood vessels of erectile tissue induced by nitric oxide released from peripheral neurons. It does this by prolonging the effect of the nitric oxide induced, newly formed cyclic GMP. As indicated above, the action of cyclic GMP is terminated by its metabolism, which is catalyzed by the enzyme, phosphodiesterase type-5. Viagra inhibits this enzyme, thereby blocking the chemical breakdown of cyclic GMP. Therefore, after Viagra administration, cyclic GMP can accumulate in sufficient quantities to permit erectile tissue arterial dilation. The resulting increase in blood flow into erectile tissue causes swelling resulting in an erect penis. It should be noted that Viagra will only be effective in a sexually excited individual. What this means is that Viagra will only be effective if neurons are actively firing and producing and releasing sufficient nitric oxide to stimulate the formation of cyclic GMP in smooth muscle. Viagra will not enhance erections if neurons are not actively releasing nitric oxide or if blood vessel walls are so damaged (atherosclerosis) that they are unable to dilate. Interestingly, Viagra has been reported to be effective under a variety of circumstances. For example, some men with spinal cord injury (impairment in nerve impulses to peripheral tissue) are reported to be helped in achieving an erection with Viagra. In addition, some men with psychological problems but without an obvious organic disorder are also reported to be helped by the drug. It, therefore appears that in both of these conditions, the individual can be sexually excited, and nitric oxide can be formed, released from peripheral neurons, and induce smooth muscle relaxation in blood vessels of erectile tissue.

Sildenafil (Viagra) and Female Sexual Dysfunction

After Viagra was deemed to be successful in treating male erectile dysfunction, the question was raised whether Viagra would also be effective in treating sexual dysfunction in women. Viagra would be expected to have the same effect on erectile tissue in women as it does in men. Thus, the erectile tissue in women (clitoris and labia) is almost identical to the erectile tissue of the penis and is controlled in the same way by parasympathetic nerves which release nitric oxide. In addition, phosphodiesterase type-5, which metabolizes cyclic GMP, is found in human clitoral erectile tissue, and this activity can be inhibited by sildenafil (Viagra). Consequently, it was expected that Viagra would produce the same increase in genital blood flow in women as it does in men. However, the importance of enhanced genital blood flow in relation to sexual dysfunction in women is unclear. Sexual dysfunction in women has always been considered by experts in this field to be more complex than that in men and attributed more to psychological problems than physical problems (such as insufficient genital blood flow). Remember, Viagra does not stimulate sexual desire and excitement; rather, desire and excitement must be present in order for the drug to be beneficial. If psychological problems constitute the major factor responsible for sexual dysfunction in women, than it should not be expected that an increase in genital blood flow would reverse sexual dysfunction?

The major conclusion of studies to date on the effect of Viagra in women is that the drug is not a universal panacea for sexual dysfunction. While Viagra appears to increase genital blood flow and vaginal lubrication, it did not produce a statistically significant reversal of sexual dysfunction. Interestingly, the studies illustrate the importance of comparing the effects of Viagra with those produced by placebo (inert drug). In one study in post-menopausal women, 25% of the subjects taking Viagra claimed improvement in overall sexual function. Although a placebo group was not tested, the improvement in function of these subjects was interpreted as a placebo effect. This conclusion was supported by a much larger trial sponsored by Pfizer, the company that produces Viagra. This study was conducted double-blind in which neither the participants nor the physicians knew which women were getting Viagra or placebo. Approximately 30-50% of women that received either Viagra or placebo claimed that their sexual function was improved, and there was no statistical significance between the responses of the drug-treated and placebo-treated groups. This suggests that the effectiveness of drugs on sexual function may depend to a large extent on the expectations and beliefs of users. Actually, this is not a surprising observation, since placebo effects are an important part of the therapeutic response to Viagra in males. The Viagra studies suggest that while the drug can increase blood flow to erectile tissue in females, this effect is not associated with an enhancement in sexual desire, arousal, or the ability to achieve orgasm. Thus, these observations suggest that for women psychological influences are more important than physical influences in determining sexual dysfunction.

Do the results of these studies mean that Viagra is ineffective in treating all types of sexual dysfunction in women? The answer is no. Studies completed to date do not exclude the possibility that Viagra may be useful in treating certain subgroups of women with sexual problems. Thus, Viagra may be effective for certain conditions. It was reported in a Newsweek article that one researcher from the Pfizer study felt that this study may have incorporated women with too many varied complaints to be definitive on the issue of the effectiveness of Viagra in treating certain types of sexual dysfunction. In support of this statement, it has been reported that Viagra is beneficial in women with normal arousal patterns whose sexual dysfunction is related to pelvic trauma or surgery, such as hysterectomy. Its effectiveness in women after hysterectomy suggests that some peripheral neurons are intact and can mediate arousal. In addition, Viagra may be effective in postmenopausal women who are receiving hormone replacement therapy (estrogen and testosterone). It is still an open question whether Viagra is effective in treating sexual dysfunction in women with specific neurological disorders, including spinal damage? As mentioned above, the drug has been reported to be beneficial in some men with spinal injuries. Viagra has also been shown to be effective in treating women who experience sexual dysfunction produced by using certain antidepressant drugs. Selective serotonin reuptake inhibitors (Prozac, Zoloft, Paxil, Luvox, Celexa) may produce a decreased sex drive and a decreased ability to achieve orgasm. Viagra is reported to reverse the latter effect. This suggests that the decreased difficulty in achieving orgasm associated with the use of these antidepressants may be related to a decrease in nitric oxide formation and release from neurons.

Other Drugs Used or Tested for Sexual Dysfunction

Aside from Viagra, what other drugs are now being used or tested for their effects on sexual dysfunction? To my knowledge, the following drugs are postulated to be useful in treating sexual dysfunction.

Phentolamine medylate (Vasomax) is an oral medication that is used to treat male erectile dysfunction. This drug antagonizes the constrictor effects of norepinephrine on blood vessels supplying erectile tissue by blocking alpha-1adrenergic receptors on arterial smooth muscle. As a result, there is increased blood flow to erectile tissue. Vasomax is likely to produce the same effects as Viagra. While, unlike Viagra, Vasomax can be used if the patient is also taking nitroglycerin or other nitrates, this drug may produce a higher incidence of hypotension. Its effectiveness in treating female sexual dysfunction is an open question.

Prostaglandin E (Alprostadil) is a substance that has been used locally to increase blood flow to erectile tissue in males. The drug, under the trade name, Caverject, is injected directly into penile erectile tissue (the corpora cavernosa), which then dilates blood vessels of erectile tissue, resulting in the rapid development of an erection. This effect lasts approximately 1-2 hours. Unlike the effects of Viagra and Vasomax, the erection produced by prostaglandin E is maintained regardless of sexual stimulation because it is not dependent upon peripheral nerve activity and nitric oxide formation and release. It will even be maintained after ejaculation has occurred. Prostaglandin E can be applied as an ointment, cream, or transurethral suppositories. While I am unaware whether this drug has been tested in women, it would seem that it could be used by topical administration or by suppository to increase blood flow to erectile tissue in women. Its effectiveness in treating sexual dysfunction in women is not likely to be better than Viagra.

Apomorphine (Uprima) was in trials for erectile dysfunction in males; however, it has recently been withdrawn by the manufacturer. This is a new dosage form of apomorphine, which is available as Zydis for the treatment of Parkinson's Disease. It is useful for this disease because apomorphine directly activates dopamine receptors in the brain. When used for erectile dysfunction, Apomorphine (Uprima) is taken sublingually (under the tongue) prior to sexual activity. While the exact mechanism of action of this drug is not known, it is thought to enhance sexual desire and arousal by activating receptors for the neurotransmitter, dopamine, in the nucleus accumbens and paraventricular nucleus of the hypothalamus. This compound might be useful in treating psychologically-induced sexual dysfunction in women. The major side effects of apomorphine are nausea, vomiting, hypotension and fainting. The manufacturer has indicated it will resubmit its application at a later date.

The hormone, testosterone, appears to increase sexual desire in women whose desire is reduced, possibly due to a deficiency in endogenous androgen levels. It has been reported that women who receive very low doses of testosterone (1/10th of the dose given to males) experience an increase in sexual desire. There are different ways of administering testosterone, including injection, topically, sublingually (under the tongue), and orally. While oral preparations are available, they are generally not recommended because of the danger of testosterone impairing liver function. Recently, it has been reported that a combination androgen/estrogen replacement therapy improved sexual desire to a greater extent than estrogen replacement therapy alone or placebo. Thus, this might be a legitimate way of reversing sexual dysfunction caused by a lack of sexual desire.

Bupropion (Wellbutrin and Zyban) is an antidepressant drug that blocks the reuptake of released dopamine in the brain, thereby increasing dopamine transmission. Drugs that enhance dopamine transmission are generally associated with an increase in sexual functioning. For example, psychostimulant drugs, such as amphetamine, methylphenidate, ephedrine and cocaine, appear to enhance sexual desire and drive. Since dopaminergic activity in the brain is involved in the experience of pleasure (nucleus accumbens) as well as sexual functioning (paraventricular nucleus), bupropion would be expected to exert a positive influence on sexual desire and drive. The results of trials with this drug have been positive. In addition, bupropion has been used effectively in reversing the sexual dysfunction caused by the selective serotonin reuptake inhibitor antidepressants.

Yohimbine (Yocan, Aphrodyne, Yohimex) is a drug derived from the bark of a West African evergreen tree that has been used to treat erectile dysfunction in men. Yohimbine is believed to act in the peripheral and central nervous systems to improve erectile function. In the periphery, the drug blocks a type of alpha-adrenergic receptor (alpha-2 receptor) located on the smooth muscle of arteries, thereby preventing the constricting action of the neurotransmitter, norepinephrine. The resulting dilation increases the blood flow into erectile tissue. The drug also increases acetylcholine release from neurons, further constricting penile veins, which prevents outflow of blood from erectile tissue (see above). In addition to peripheral effects, the drug is thought to act in the central nervous system to increase sexual desire. As yohimbine can produce a variety of adverse effects, its use requires medical supervision.