Centrally Acting Oral Therapy

19 May

Centrally Acting Oral Therapy

Apomorphine:       Apomorphine is a drug used routinely in the treatment of patients with Parkinson’s disease. Empirical evidence from a few Parkinson’s patients treated with apomorphine has suggested that they experience increased sexual activity (76). Male patients with alcohol dependence treated with the same  agent  have  also  reported  improved  erectile  function  (77).  Data  from these two groups of patients suggest that apomorphine is able to induce erections.

While apomorphine is a derivative of morphine, it has greater structural and pharmacological similarities with dopamine, and acts as a dopamine agonist (78 – 80) (even in urine screening for opioids, apomorphine will rarely give a false positive). Dopamine and apomorphine act centrally on dopamine receptors (especially D1 and D2), and studies using rodents have demonstrated a role for dopamine in the control of sexual function in both sexes (76). This means that this drug works via a very different mechanism than most other pharmacological agents used in the treatment of ED. As we have already seen, many other agents act locally on smooth muscle to increase blood flow to the penis. While the exact mechanism of action of apomorphine is not fully understood, it appears to work on several areas of the brain to boost the neuronal signal involved in the erectile response (76). Recent large-scale trials have confirmed the connection between dopamine and sexual function in men because apomorphine is able to induce penile erections when they are sexually stimulated (81).

Apomorphine can be used to treat men with physical or psychological etiologies. It is important to note that like other oral treatments in use for ED, this drug requires the man to become sexually stimulated before an erection can be achieved. In this setting, apomorphine is self-administered sublingually (apo SL) as a 2 or 3 mg single dose, usually starting at 2 mg and only increasing to 3 mg if necessary (79,80). Good patient education is important to achieve optimum results. The tablet is placed under the tongue after a sip of water and allowed to dissolve slowly for up to 10 min without swallowing it. Best results are often not achieved until use of apo SL on the sixth occasion (82). By this point, over 90% (80) of correctly diagnosed users will achieve an erection and the majority of these  will be within 20 min, making this a fast acting drug. This response is repeatable, so that by the sixth month of use there are still  .90%  of  men  able  to  achieve  erections  firm enough  for  intercourse [assessed using data from diary records from a double-blind placebo-controlled trial (81)].

Apo SL is rapidly absorbed and eliminated, and reaches a peak plasma con- centration within 40 – 60 min, having a half-life of    2 – 3 h (79). This means that apo SL can be taken every 8 h if required. Data suggests that no dose adjustment is required in elderly patients although this group is more prone to hypotensive episodes. There are few contraindications for use. Impaired hepatic function and renal insufficiency are not necessarily contraindicated but the dose should be limited to 2 mg. More work needs to be done in these areas, and until such time  a  careful  assessment  should  be  made  to  balance  benefit against  risk, especially in patients with hepatic insufficiency. There is also further work to be done to assess efficacy in patients with SCI and multiple sclerosis. The effect on patients who have had prostatectomy or pelvic surgery is also not known. Caution should be taken when treating patients with uncontrolled hyper- tension and patients with hypotension. Antihypertensives and nitrates (especially short-acting nitrates) do have the potential to cause an acute episode of hypoten- sion. Caution also needs to be taken in patients who have penile deformity or other conditions that may predispose them to priapism. There are few absolute contraindications for use, but include combinations with other dopamine agonists or antagonists and patients with severe unstable heart conditions or other con- ditions where any  sexual activity  creates  unacceptable  risk. Excess alcohol should be avoided due to the increased risk of hypotension.

Because of the low doses involved in the therapeutic use of apo SL in the treatment of ED, there are few side effects (80). The most commonly seen are nausea (6.8%), headache (6.7%), and dizziness (4.4%). Nausea tends to diminish with subsequent dosing, so that by the eighth dose this is usually no longer a problem. Where nausea and emesis is a concern, it is safe to prescribe ondanse- tron hydrochloride, prochlorperazine maleate, or domperidone prophylactically (79). No other antiemetics have been tested for safety. Rhinitis and pharyngitis have been reported in a very small proportion on men, and in a very few cases (0.2%) syncope can occur.

There is more work to be done concerning the use of apo SL. But data published to date do indicate a good response (82,83). Responses from ques- tionnaires such as the IIEF indicate that many patients and their partners report erectile function sufficient for penetration. The rapid onset of apo SL allows for a fair degree of spontaneity, and the response is predictable once satisfactory success has been achieved. This agent is available in the UK and Europe.

Yohimbine:    Yohimbine (84) is an alpha2-selective antagonist currently unlicensed for use for men with ED. It is a naturally occurring alkaloid produced from the African yohimbe tree. It has been implicated as an aphrodisiac (85) but has not been properly considered as a therapeutic agent until recently. The pro- posed mechanism of action of yohimbine is to block presynaptic alpha2 receptors while sparing the postsynaptic alpha1 receptors. The effect of this is to enhance the release of norepinephrine in the central nervous system. It reaches a plasma concentration in just 10 – 15 min and has a very short half-life of just over 30 min. Previous research has shown that oral yohimbine can be used successfully to treat ED with a psychological basis. It has also been used to reverse antidepressant- induced sexual dysfunction.

Guay and Spark (84) suggest that previous studies using yohimbine have not been successful because their subjects included a large proportion of men who were smokers. They hypothesized that smoking reduces the effectiveness of yohimbine and so their study excluded this subgroup. In their small-scale study of 18 men aged between 34 and 69 years, they reported that use of low doses of yohimbine (5.4 or 10.8 mg) at home had resulted in nine of the men achieving successful penetration on 75% of occasions tried. They reported few side effects  with the  low doses used (mild anxiety  in  one subject and hot flashes in another). Also noted was a slight increase in serum cortisol. From their evidence, they suggested that yohimbine could be useful for a subset of men with mild disease or few risk factors, and recommended that yohimbine should be studied further. Random controlled trails would be useful to determine the safety and efficacy of this established pharmaceutical agent.

Second Line (Injectable  and Intraurethral) Treatments

Injectable and intraurethral treatments for ED are now considered to be second line treatments after oral therapies have been tried or rejected. Also, these treat- ments are primarily for men with an organic cause for their ED. Patients need to be made aware of the potential for priapism. The initial doses of these agents are given under supervision as there is also a risk of a hypotensive episode needing medical attention. Patients must be taught how to inject safely and using a proper technique so as to avoid the problems of fibrosis which indicates that treatment must be discontinued.

Only alprostadil (prostaglandin E1) is licensed for use as an intracavernosal injection (ICI) in the UK and US. This drug utilizes cyclic adenosine mono- phosphate (cAMP) rather than cGMP (see Fig. 7.1). Prostaglandin E1 (PGE1) receptors are G-protein coupled receptors located at the surface of the smooth muscle cell. When stimulated, they activate adenylyl cyclase via the G-protein. This increases the concentration of intracellular cAMP, which acts as a second messenger in a cascade that ends with a decrease in intracellular calcium concen- tration and muscle relaxation. No sexual stimulation is required to elicit an erec- tion using the ICI route of delivery. ICI alprostadil is marketed as 5, 10, 20, and 40 mg injections that have been proven to be effective and safe doses to give in the majority of cases (86). At the time of Linet and Ogrinc’s studies, little else was available in the way of pharmacotherapies for ED. In the dose – response study of 296 men with various etiologies, they found that the erections would last  longer the higher the dose injected.  This pattern  was repeated in their other placebo-controlled experiments with increasing numbers of subjects to determine optimum dose and to confirm efficacy and safety. In the largest of the trials with 683 men, 69% completed the 6 month study. There are adverse affects associated with ICI alprostadil use. The treatment was discontinued by 6% of men due to the main side effect, which is penile pain. This effect was actu- ally experienced by half of the men participating, but not on all occasions. Most often, the men reported the pain as being mild. Five percent of the subjects experienced prolonged erections although most men continued the treatment. In the three studies, six individuals experienced priapism (an erection lasting .6 h). In the large study, 87% of men reported satisfactory sexual activity, and this was reflected in the partner’s questionnaire. Other rare adverse effects occurred in 1% of the men and were thought to be related to hypotension. These included irregular pulse, lightheadedness, dizziness, diaphoresis, vasodila- tion, and vasovagal reaction. It is for this reason that the initial prescribed dose must be delivered in the clinical setting under medical supervision.

Alprostadil can also be delivered intraurethrally as MUSE (medicated urethral system for erection). This mode of delivery is recommended for a small subset of individuals who may have problems with injecting. PGE1 is deliv- ered into the urethra immediately after urination (for lubrication and to help dis- perse the drug) using an applicator which the patient can be taught to use safely. Here, the drug is used at a much higher concentration at 125, 250, 500, or 1000 mg doses. Researchers have reported very different efficacies using MUSE in this way (87 – 89). Only Padma-Nathan et al., used a random controlled trial, and their subject recruitment was far greater than the other two groups (1511 vs. 100 and 103).  Werthman  and  Rajfer  (87)  only  reported  making  observations up  to 10 min after administration of the drug whereas Padma-Nathan et al. (89) made observations up to 60 min after drug delivery. Also, Werthman and Rajfer’s studies were conducted entirely in the clinical setting, which can inhibit the erec- tions elicited by MUSE which often require sexual stimulation. Padma-Nathan et al., found that 65.9% of subjects had maximal penile responses (assessed on scale of 1 – 5) in the clinical setting. They increased the dose delivered to each indi- vidual up to a maximum of 1000 mg. The number of men achieving the maximum penile response rose linearly with increasing dose. Of this group, 35.7% of men experienced penile pain which was usually mild; 2.4% withdrew from the study because of the pain. Hypotension occured in 3.3% of the men, and syncope in 0.4% (for this reason, the initial prescribed dose must be delivered in the clinical setting under medical supervision). The study continued by giving further subjects MUSE to use in their own home. A 3 month trial of MUSE, was completed by 87.7% of these men with ,2% discontinuing because of adverse effects. The success rate for intercourse for the home trial group was 64.9%, slightly lower than that indicated in the clinical setting. These men reported penile pain as the main adverse effect. The problems associated with ICI alprostadil, such as fibrosis, hematomas, and priapism, were not seen. Slight bleeding from the penis can occur, and this is probably due to minor trauma when inserting the MUSE appli- cator incorrectly (87).

Papaverine and phentolamine are not currently licensed in the UK for the treatment of ED, although they have been used for many years. Papaverine is closely related to morphine and originates from the opium poppy. However, its little understood pharmacology is very different from that of morphine. It is believed to inhibit phosphodiesterase in a similar fashion to sildenafil. The start- ing dose is dependent on local formulation but is usually    20 mg in the alpros- tadil nonresponder, rising in increments to 50 mg. Phentolamine is a nonselective alpha adrenoceptor antagonist with a plasma half-life of 2 h and acts to relax smooth muscles (90). The starting dose is 0.5 mg which can be repeated after 20 min if there is no response. Typically, it may be necessary to combine two or more of the agents in the nonresponding patient (hence the tri-mix preparation). Injection into the cavernosal tissue is self administered after a clinic based trial of the drugs (often in combination with each other) under medical supervision. As with ICI alprostadil, complications can arise from repeated injections into the same site. These include nodule formation and indurations of the tunica albuginea resulting in a Peyronie’s-like distortion of the penis. These affects should be checked for on follow-up visits. The nodules are painless and become more likely to occur as treatment continues over time (91). These complications along- side dislike of the technique by the man and his partner as well as “needle phobia” (increasing adrenergic outflow), all lead to a limited use of these effective agents.

Moxisylyte is  an  injectable  alpha-blocking agent  and  is  useful where there is considerable psychological etiology requiring evidence of an erection. Effective  salvage  therapy  for intracavernosal injection nonresponse includes augmentation with sildenafil (92) or other combination therapies.

Third Line Therapies

Vacuum  constriction   devices  and  constriction   rings  for  men  with ED:            A vacuum constriction device (VCD) (93) is simply a rigid tube that is placed over the penis. A vacuum is then created inside the tube either manually or by a battery-powered motor. The penis becomes erect when such a negative pressure surrounds it. This principle is not new, and was being used as a treatment for ED as far back as 1874. For some men, this vacuum is sufficient, but others need a “constriction ring” which when applied to the base of the erect penis, preventing venous leakage once the tube is removed for sexual activity to commence.

This device is useful as a treatment for men with ED who are unable to use oral therapies. It also avoids the use of ICI therapy, which some men find objec- tionable. It is fairly simple to use although it is somewhat obtrusive. One drawback of use with the constriction ring is that the erection pivots about the ring making it less natural. Its use has been studied in men with diabetes, SCI, explanted penile prosthesis, and requiring dialysis for various reasons. These studies have all reported high success rates of VCD use with approximately three-quarters of men. Partners too find the device an acceptable compromise.

As with all of the treatments, there are some contraindications to the use of VCDs. Sickle cell trait/disease, leukemia, and anticoagulation therapy are medical considerations that can be complicated by VCD use. In addition, men with poor manual dexterity may find the manual pump and the constriction ring difficult to use, although this need not be a problem for men with obliging partners!

For a few individuals who are able to achieve an erection but not maintain it, they can use the constriction ring without the vacuum tube. This will enhance the firmness and size of the penis. In all cases where a constriction ring is used, a time limit of 30 min must be strongly emphasized.

Some adverse affects are reported by some individuals using VCDs, but these tend to be painless and self-correcting. Ecchymoses is reported in 12% of users, and 25% report petechiae. Other effects that can put some men off the idea include cold/numb penis, lack of ejaculation, pivoting of the penis and altered sensation at orgasm, which may be uncomfortable.

As with other treatments, VCD may be combined with other therapies to augment response such as with MUSE or psychosexual therapy (94).

Psychological  Therapies  for Men with ED

In the majority of cases of ED, psychological factors are involved in either the devel- opment of the disorder or the maintenance of the problem. While recognising that many men would not seek a psychological approach to resolving the condition, an outline of performance anxiety about continued erectile failure and the effect this has on their partner and their relationship, is often appreciated by the man. Difficulties with communication and the development of suspicion and mistrust between partners may need discussion, recognition, and specific intervention.

One group of men will experience ED almost entirely related to disease pro- cesses. These men are likely to have good interpersonal relationships which, if longstanding, will have been maintained with communication, respect, and inti- macy. They are unlikely to need much in the way of sex counselling (if any).

A second group of patients will have ED as a consequence of a disease state but where there are also contributory psychological factors. Acknowledging with the patient that the ED may be having an adverse effect on his overall sex life may facilitate an interaction with the man (and often his partner) to find ways to re-establish the desired sexual relationship. Sometimes this will involve pro- vision of basic educational information and guidance to enhance the sexual relationship. It may also be appropriate to consider a more integrative approach with the short-term prescription of an erectogenic agent to help restore sexual confidence and function.

The third group of men includes those with the presence of other psycho- logical morbidity such as dysthymia or mild depression, substance misuse, rela- tional problems, or other sexual problems such as loss of desire or ejaculatory disturbance. These may require a more proactive input from the psychosexual therapist, which may incorporate psychosexual therapy, relationship therapy, often integrated with management from one or more mental health professionals for any associated mental health disorders.

In each of these three situations, an integrative approach by the assessing clinician to ensure adequate  assessment of both psychological and physical contributing factors may lead to more efficacious outcomes while recognising that the interventions themselves may be multiple, rather than relying on one treat- ment and progressing in a linear fashion to alternatives because of failure of “first line therapy.” Helping the man to start to use his preferred treatment choice (such as sildenafil) and integrating this into his sexual repertoire with his partner can help the man and the couple to restart their sexual lives together and regain not only a good erection, but also good sex.

Psychosexual  and Relationship  Therapies  for Men with ED

The clinician should try to encourage the man to be open and honest with his partner. This will allow the couple to identify together any anxieties or other issues that might be causing the problem. It is important to provide sufficient time for a psychosexual assessment and this is likely to be     1 h. This will address predisposing, precipitating, and perpetuating factors.

Predisposing factors will include limited sexual education and childhood and pubertal sexual experiences including traumatic episodes of any kind and general life stressors. Environmental stressors may need addressing, such as financial, domestic, or children-related issues.

Common precipitating factors include deterioration in the general relation- ship; separation, divorce, or recent death of a partner; vocational failure; and onset of physical or psychiatric illness.

Sometimes there can be problems in their relationship. Couples therapy helps both partners to address the situation and this may be necessary before any specific psychosexual therapy. Issues may be limited to poor communication skills and ways of relating together but there may also be difficulties in other areas  such as negotiating  time  apart (or together)  or deciding the  share of household duties. Systemic psychotherapy may be indicated.

There may be specific performance anxiety about recurrence of erectile dis- order even after just one or two episodes (e.g., attempts at love making while intoxi- cated with alcohol), which maintains the problem. There may be fear of repeated failure with associated guilt and embarrassment. Once the problem has become established, a number of other maintaining factors may need addressing during therapy. Themes include loss of attraction to the partner, poor communication of likes and dislikes during foreplay and sex between the partners, limited sexual edu- cation and awareness, a fear of intimacy, and an impoverished self-image including concern about genital size (particularly penis size). There may be unrealistic expec- tations from sex as well as other lifestyle, cultural, and religious restrictions on sexual variety. Attraction towards others of the same sex may become evident.

Therapy is directed toward the relationship with agreed and realistic goals of therapy established fairly early in therapy. Specific techniques such as genital self-focus work and modified sensate focus may be helpful. Where therapy is successful, attention to relapse prevention work is recommended. A detailed description is provided elsewhere (95).

Comorbid sexual problems such as secondary early ejaculation or loss of desire as well as other psychological problems such as depression or social phobia and anxiety may be evident on assessment, which will require input from a sex therapist or mental health professional. Techniques including cogni- tive and behavioral therapy or psychoanalytical therapy may be indicated.

Integrated Therapies

Several workers have reported success from a combination of psychological and physical treatments for ED including sex therapy and ICI (96,97), psychotherapy and ICI (98,99), couple psychotherapy and VCD (94,100), sex therapy and sildenafil (101), short-term therapy and ICI (101), and ICI and counselling (102).

Other Unlicensed Treatment Therapies  for Men with ED

Several new formulations are being developed, such as topical alprostadil and intra- nasal apomorphine. New agents are being developed, including selective PDE3/4/

5  inhibitors:  MS-223131  (Bristol-Myers  Squibb),  T-1032  (Tanabe  Seiyaku), TA-1790 (Vivus), sildenafil nitrate (NCX-911) (NicOx); nonselective inhibitors of postsynaptic alpha-adrenoceptors within the corpus cavernosum: phentolamine (Vasomax; Schering Plough), melanocortin receptor agonists such as melatonan II (Palatin) (s.c. and intranasal)—increases erections and sexual drive/appetite (phase 2A)—and the 5HT1 agonist VML670 (Lily/Vernalis).

A recent review of herbal remedies has been scrutenized for potential benefit (103). Examples include L-arginine, yohimbine, and extracts of Tribulus terrestris L. (Protodioscin) that is metabolized to DHEA and which is reported to increase both erections and sexual drive.

Treatment for Priapism

For erections lasting over 4 h, apply cooling agents to the genitals and encourage moderate exercise to the legs to divert blood to the lower limbs. If the erection remains,  aspirate  20 – 50 mL  of  blood  from  the  corpus  cavernosum  using  a 19 – 21 gage butterfly using a sterile technique. This may be followed by irrigation with heparinised saline. If necessary, repeat to the other side. If there is no response proceed to ICI alpha-adrenergic agents. Either phenylephereine [10 mg (1 mL) vial diluted to 10 mL with saline and 0.5 mg (0.5 mL) injected at a time to a maximum of 10 mg (10 mL)] or ephedrine [30 mg in 1 mL vial, using 15 mg (0.5 mL)] should be given, and repeated once if necessary. Monitor pulse and BP continuously. Proceed with extreme caution in patients with coronary heart disease, uncontrolled hyperten- sion, or cerebral ischemia and in men taking MAOIs as hypertensive crises may occur. See also the latest AUA guidelines (104).

Surgical Interventions for Men with ED

Vascular Surgery

Penile arterial revascularization is only appropriate in young patients with demonstrable arteriogenic ED due to congenital vascular anomalies or traumatic injuries to the pudendal or penile arteries (e.g., after road traffic accidents).

Prostheses

There are three forms of penile prostheses available: semi-rigid, malleable, and inflatable. Typical candidates for a penile implant are patients with chronic disease states such as long-term diabetes and end-organ failure or severe arterio- genic impotence combined with severe veno-occlusive dysfunction and men with treatment unresponsive Peyronie’s disease in combination with ED. Typical complications  of  prosthetic  surgery  are  infections  (1 – 5%)  and  mechanical failures (10 – 20%)

Special Situations  Requiring Interventions for Men with ED

Depression  and Serotonin Reuptake Inhibitors

Sexual dysfunction associated with the use of serotonin reuptake inhibitors has been reported in 30 – 70% of treated patients and is a significant contributor to discontinuation of these medications. A review of selective phosphodiesterase type-5 inhibitors for antidepressant-associated sexual dysfunction suggests treatmet of this side effect of antidepressant medication could improve depression disease management outcomes (105).

Testosterone  Deficiency

Androgen replacement can improve libido, erection rigidity, and sexual satisfac- tion in men with demonstrable low serum levels of testosterone (106). In a large cohort of 1461 men presenting with ED, just over one-sixth (17.7%) at initial screening had biochemical evidence to suggest the possibility of hypogonadism. More rigorous estimation of serum testosterone, associated parameters, and the presence of clinical symptoms resulted in 3% of the population having a diagno- sis of hypergonadotropic hypogonadism. Of these, one-fifth agreed to a trial of testosterone therapy but two-thirds of this eligible group also required another erectogenic agent to resolve the ED (107).

Treatment can be with daily 5 mg transdermal patches or gel or 250 mg intramuscular injection three times weekly. The  dose may  need  adjustment depending on  clinical  and  biochemical  response. Monitoring of  hematocrit, liver, prostate, and lipid parameters is mandatory.

CONCLUSION

ED  is  the  most  commonly  presenting  male  sexual  problem  to  clinicians. A  thorough  assessment of  possible  etiological  factors  and  consideration  of psychological, couple, and physical factors in the management of this disorder will allow sufferers of the condition an excellent opportunity for amelioration of the symptom. In many instances reassurance, educational advice, and the use of a PDE5 inhibitor will be sufficient as first line management of the condition.

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