Drop-Out Reasons and Complications in Self-Injection Therapy with a Triple Vasoactive Drug Mixture in Sexual Erectile Dysfunction

Home , Trimix (drug)

Drop-out reasons and complications in self-injection therapy with a triple vasoactive drug mixture in sexual erectile dysfunction

A CasabeÂ, A Bechara, G Cheliz, S Romano, H Rey and N Fredotovich

Sexual Dysfunction Section, Division of Urology, Hospital Durand, Buenos Aires, Argentina

The usefulness, complications and reasons for discontinuing the self-injection program with a combination of papaverine, phentolamine and prostaglandin E1 were evaluated in 189 patients (mean age 57.2 y), who were included from April 1993 to September 1995 (mean follow-up 10.25 months). Patients were split into two groups: Active, those who continued with the program (48%); and Inactive, those who discontinued treatment or failed to attend consultation after ®ve months from the last visit (52%). Only 30% of the inactive group reported failure to achieve response with the self-injected doses. Fibrosis in 5.3% and prolonged erection in 3.7% were the most severe complications. Patients lacking organic pathology showed a clear tendency to reduce the drug dose during treatment, recover spontaneous erections and discontinue the program for reasons unrelated to drug ef®cacy. The triple drug mixture provides an effective alternative in the treatment of impotence, with a low rate of complications.

Keywords: papaverine; phentolamine; prostaglandin E1; self-injection; drop-out reasons

Introduction Diagnostic studies carried out included psychosexual, vascular (pharmacological erection test, penile color ¯ow duplex ultrasonography, caverno- A self-injection program with vasoactive drugs sometry-cavernosography), neurological (emg-cc, (VAS) for the treatment of sexual erectile dysfunc- somatic nerves evaluation) and endocrinological tion (SED) is a widely used and recognised meth- (free testosterone and prolactin) evaluation, as well 1±5 od. as determination of nocturnal erections with Rigis- Several drugs have been employed, including can (Dacomed Corp., Minneapolis, Minnesota, 6 papaverine with or without phentolamine, prosta- USA), with due attention to individual patient 7 glandin E1 (PGE1) and more recently the combina- features as previously described.9 8 tion of these drugs. Organic pathology was diagnosed in 105 patients The aim of the present work was to evaluate the (55.6%), while SED was purely functional in the usefulness of a mixture of three vasoactive drugs remaining 84 (44.4%). Forty-six patients (24.3%) (TRIMIX), the complications associated with its use, were treated concomitantly with sexual therapy. and the reasons for discontinuing treatment with The organic group was constituted by 72 patients VAS. with vascular pathology, 21 diabetics, 7 neurologics and 5 with pelvic traumatism. The dose of trimix to be taken by the patients was Patients and methods determined after a phase of progressive testing, starting with 0.25 ml in functionals and with 0.50 ml in organic patients. This dose was gradually During the period from April 1993 to September increased or decreased until they reached a rigidity 1995, a total of 189 patients with SED, whose that would enable a penetration of at least 20 min. average age was 57.2 y (range 27±78 y), were eval- All the patients were injected and they underwent uated and included in a VAS program with TRIMIX. and erotic manual and visual stimulation for 15 min. The response was evaluated by the physician in charge. Correspondence: Dr A CasabeÂ, Av. Santa Fe 1379-1, (1059) Buenos Aires, Argentina. Once VAS dose was determined and method Received 13 August 1996; revised 11 February 1997; accepted training was completed, patients were recalled for 4 17 April 1997 quarterly control as already described. Drop-out reasons and complications in self-injection therapy A CasabeÂ et al 6 Throughout, a mixture of vasoactive drugs (TRI- Table 1 Reasons given by inactive group responding to the MIX) was employed, prepared as follows: 17.64 survey for discontinuing self-injection program (50 patients) mg/ml of papaverine hydrochloride, 0.58 mg/ml of Recovery of erections 15 (30%) phentolamine mesilate and 5.8 mm/ml of PGE1. No response achieved 15 (30%) According to follow-up ®ndings, patients were Rejection of method 10 (20%) split into two groups: (a) Active Group, those who Loss of sexual partner 5 (10%) Development of further dysfunction 3 (6%) continued with the VAS program as treatment for Deterioration in general status 2 (4%) their dysfunction; and (b) Inactive Group, those who failed to attend control after ®ve months from the last consultation or who at successive controls expressed their decision to discontinue treatment. Table 2 Reasons given for discontinuing self-injection program We have not included in the inactive group those according to diagnosis (50 patients) patients who had to discontinue treatment due to Reason Functional Organic complications following the VAS program. Surveys were conducted in order to detect the Recovery of erections 14 (93%) 1 (7%) causes of discontinuing the VAS program of the No response achieved 5 (33%) 10 (67%) inactive group, which were performed during con- Rejection of method 6 (60%) 4 (40%) Loss of sexual partner 4 (80%) 1 (20%) sultation or by telephone. Development of further dysfunction 3 (100%) 0 Deterioration in general status 0 2 (100%)

Results Out of the group of patients reporting failure to achieve good response with TRIMIX, 67% presented The active group was made up by 91 patients (48%), organic pathology as a cause of their dysfunction, out of whom 66 (72.6%) presented organic and 25 while among those who recovered rigid erections, (27.4%) functional pathology. 93% were functional cases (Table 2). The inactive group comprised 98 patients (52%), Complications observed in the total patient 39 (40%) with organic and 59 (60%) with functional population on the VAS program (n 189) were as pathology. follows: echymosis or hematomas at the injection Concomitantly, sexual therapy was carried out on site (20.1%), ®brosis (5.3%), prolonged erections 27 patients belonging to the active group (29.7%) lasting over 3 hours (3.7%) and urethral bleeding and on 19 of the inactive group (19.4%). (1.1%). Prolonged erection episodes resolved within Mean follow-up was 10.25 months for the global 12 h after onset of the symptom, and no cases population, 16.95 for the active group and 4.32 presented evidence of ®brosis in the cavernous months for the inactive group. bodies as a sequela. Out of the total number of patients included in The 10 patients who presented ®brosis, which the VAS program, the triple mixture maintained appeared after 3±9 months of treatment, were self- active response in 159 (84.4%) during the observa- injecting doses ranging from 0.125±0.75 ml. Out of tion period. these, 50% presented diffuse cavernous ®brosis, The mean dose of TRIMIX employed at the located in all cases on the homolateral side on the beginning and end of the treatment was 0.58 and punctions site, with a variable extension ranging 0.42 ml, respectively with an average time of dose from 2±4 cm while the other 50% had subalbugin- variation of 3.22 months. This decreasing trend was eous nodules. also discerned in the active group (0.55±0.43 ml) as None of the patients on the VAS program well as in the inactive group (0.46±0.31 ml). Patients complained of pain during the therapeutic phase. with functional pathology presented a mean dose variation of 0.59±0.28 ml, while for those with organic pathology it was of 0.59±0.55 ml. Out of the surveyed patients in the inactive Discussion group, 50 (51%) responded, 19 in consultation and 31 by telephone. Reported causes of discontinuance were: (a) The ideal vasoactive drug must be easy to apply and recovery of spontaneous erections in 15 (30%); (b) manipulate both for the physician and for the inability to achieve erections suitable for penetra- patient, possessing a high therapeutic index and a tion in 15 (30%); (c) rejection of the method in 10 wide therapeutic range, as well as lacking pharma- (20%); (d) loss of the sexual partner in 5 (10%); (e) cological interactions, toxic or adverse effects. development of further dysfunction (either of desire Obviously enough, such a drug is not yet available. or of ejaculation) preventing sexual activity in 3 In theory, the low volumes employed when using (6%); and (f) severe deterioration in general status in mixtures of 3 or more vasoactive drugs would be 2 (4%) (Table 1). expected to reduce the frequency of undesirable Drop-out reasons and complications in self-injection therapy A CasabeÂ et al 7 side-effects of each particular drug, as for instance It is worth mentioning, we have not considered the pain associated with erection when resorting to drop-outs, those 5 patients who had to discontinue 10 PGE1 alone. the VAS program with (TRIMIX) due to the devel- Furthermore, the diverse levels of action on the opment of a ®brotic process in the cavernous body. mechanism of erection exerted by each one of these Causes of discontinuance unrelated to the ef®- drugs would presumably enhance their joint ef®cacy ciency of TRIMIX (70%) were found for the most by acting synergically.11 In our experience one ml of part among cases of functional pathology. TRIMIX proved more effective than 40 mg of PGE1 in Within this group, one third of the patients non-responders to high doses of papaverine and recovered erections suitable for penetration, out of phentolamine.10 whom 93% presented functional pathology. In our population, the triple mixture proved to be On appraising dose variation according to dys- effective in roughly 85% of the patients followed up, function diagnosis, patients with functional pathol- a ®gure comparable to those reported by other ogy markedly decreased the dose employed (from authors.12 0.59±0.28 ml), whereas patients with organic pathol- The most noteworthy observation in the present ogy failed to present signi®cant variations (from 0.58 series was the great number of patients who ±0.55 ml). The coincidence in the mean initial dose discontinued the VAS program (52%), which could was accidental, probabily due to the low dose used explain the low mean follow-up period (10.25 in neurological patients and to the high dose months) in a population under observation for over necessary to achieve the erection in the functional two years. This ®nding has been previously de- patients. scribed with lower percentages ranging from 12± Among the neurological patients we have also 50%,13±17 a difference attributable to the composi- included the diabetics and the pelvic traumatised, tion of studied populations, in which the percentage with a possible neurological erectile dysfunction. of patients with functional pathology was lower On the other hand, we believed a high dose was than 10%, considerably less than the 44.4% percen- necessary in the functional group due to the high tage recorded in our present series. adrenergic tone at the beginning of the treatment. However, in a series of 140 patients on a self- This group probably experinced lesser anxiety, an injection program with papaverine plus phentola- increase in their self-esteem, and the assurance mine or prostaglandin E1, with a mean follow-up of brought about by the recovery of erections that allow 11 months and a population comprising only 20% of penetration, even if they were pharmacologically functional patients, Weiss et al18 communicated a obtained. These reasons could account for the discontinuance rate of 80%. signi®cant progressive decrease of their dose. On evaluating patients receiving complementary On the basis of our results, it may be highlighted sexual therapy, a greater trend to remain on the VAS that the functional group was more liable to program was observed. However, it is dif®cult to discontinue treatment within a period of four claim the superiority of the combined treatment months due to causes unrelated to erectile response, since to establish comparable groups speci®c para- to vary the dose signi®cantly or to recover sponta- meters would be required to measure conditioning neous rigid erections suitable for penetration. psychological and marital factors pertinent to each This could be explained by the effect caused by patient. Strikingly, there are indeed few reports impotence symptom reversion, which offsets the documenting the rate of treatment discontinuance in psychological mechanisms at work, although the patients receiving sexual therapy alone. Some de®nitive disappearance of the symptom cannot be authors contend that no signi®cant differences ensured in this case. In our series, only 17% of the could be found in the rate of treatment discontinu- functional patients (14 out of 84) recovered rigid ance in cases with concomitant sexual therapy erections that allowed penetration. We may infer versus those without.19 that a longer follow-up would show a larger number With respect to the causes of desertion, we of recoveries. observed that the group reporting inability to achieve On evaluating the three types of observed com- erections suitable for penetration made up 30% of the plications, echymosis at the injection site required surveyed population. This might suggest that in such no special assistance by the physician in any case. cases TRIMIX had lost its ef®ciency, but this is hardly All prolonged erection episodes recorded in this tenable as it was not checked by the attending series (7 patients) were controlled by puncture and physician, since other feasible factors such as drainage with or without intracavernous injection of inappropriate drug use by de®cient application 10 mg of complementary of a-adrenergic agonists, technique, faulty preservation and/or insuf®cient clorhidrate of ethylephrine, of frequent use in divers dosing could also explain the poor response countrys in hypotensive crisis.2 achieved. However, there is the possibility that the Although the percentage of prolonged erections is considerable number of patients with organic pathol- slightly superior to others (3,7%),8;21 the reason ogy in this group (67%) could have worsened their could be found in the large number of functional disease, thus becoming refractory to vasoactive drugs. patients (44%) Drop-out reasons and complications in self-injection therapy A CasabeÂ et al 8 As regards ®brosis associated to VAS, two Table 3 Incidence of ®brosis associated to vasoactive drug self- presenting variants may be discerned: (a) small injection (VAS) subalbugineous nodules (SAN) causing neither Fibrosis Final bending nor pain; and (b) diffuse ®brosis of the Pt. Age Diagnosis Dosea type treatment cavernous bodies that may be associated to bending and/or pain as those described in the penile plastic 1 58 Functional 0.125 PPI Vacuum 2 48 Organic 0.25 PPI Prosthesis induration PPI. SAN do not pose a serious compli- 3 69 Organic 0.5 PPI Physiother. cation, since they fail to progress to extensive 4 63 Organic 0.75 SAN VAS ®brosis and are satisfactorily managed by discon- 5 72 Organic 0.75 SAN VAS tinuing treatment transiently, though on occasion 6 57 Functional 0.75 SAN VAS 7 59 Organic 0.75 PPI Physiother. they may be ameliorated by physical therapy 8 62 Organic 1 PPI Vacuum (gallium arsenide laser) or medical treatment (vita- 9 38 Functional 0.25 SAN VAS min E). In this series we have used a combination of 10 71 Organic 0.5 SAN VAS lasertherapy and vitamine E 800 mg/d in those ®ve PPI penile plastic induration. patients with SAN and those two with PPI. The SAN SAN subalbugineous nodule. disappeared in all cases. aVolume expressed in ml TRIMIX. Different results have been published by other authors who have also tried multiple physical and medical treatment in order to stabilize or improve We believe that periodic self-examination of the focal or diffuse ®brosis in the cavernous bodies.22 penis is extremely useful for early detection of Extensive penile ®brosis is a relevant complica- penile scars. tion even in patients with pre-existing organic The TRIMIX solution employed failed to present pathology, due to bending and/or pain and to the any collateral effects other than those already probable technical dif®culty in the case of opting for observed with other vasoactive drugs.1,2,11,16,17,24 a penile prosthetic implant as alternative therapy. Self-injection therapy with VAS affords a valid The genesis of such ®brosis depends on the treatment alternative in patients with SED of physic-chemical properties of the employed sub- functional and organic origin, even though the latter stance and on local penile factors as yet undeter- show a greater tendency to discontinue the VAS mined with accuracy, presenting a close correlation program. among frequency, time of use and appearance. Future investigations will no doubt evaluate, on Out of the ®ve patients in whom this phenomen- one hand, whether VAS program discontinuance on was observed, only one presented functional due to insuf®cient response is caused by actual pathology, who received treatment with vacuum refractoriness to vasoactive drugs or to improper devices; the other four patients with organic pathol- VAS use or dose, and on the other hand, whether ogy were treated with physical therapy in two functional patients with sexual therapy participat- patients, vacuum device in one and prosthesis in ing in a VAS program present a lower percentage of the remaining one. desertion. Like other authors, we also believe that vascular patients who have an insuf®cient pharmacological erection, though apt for penetration, may suffer Conclusions penile microtraumatisms during coitus, which might foster the development of ®brosis.23 Cases of subalbugineous nodules discontinued The TRIMIX solution affords a useful therapeutic treatment transiently, carrying on currently with alternative for the treatment of sexual erectile injections (Table 3). dysfunction arising from a functional or organic In 170 patients self-injected with a mean of cause, with a low rate of complications. 0.36 ml of a triple VAS mixture, Govier et al8 In this series half of the patients on the VAS recorded 4.2% of ®brosis, 3.5% of pain and 1.7% program discontinued treatment largely due to of prolonged erections. causes unrelated to erectile response. 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