The response to Uprima® (apomorphine sublingual, (apo SL)) has been well documented in conventional clinical trials. Apo SL produces a predictable, consistent and durable response across a wide variety of patients. The positive reinforcement of a successful outcome should further support clinical benefit. Apo SL with its rapid onset affords a greater opportunity for spontaneity, which can be an important factor in influencing patient choice. It is recognised that patient counselling and the setting of realistic expectations are vital to a successful outcome. The impact of persisting with sequential treatment on outcome has been calculated from the clinical data. While apo SL is effective de novo in 50% of single doses, additional benefit is observed with repeat dosing. Full benefit may not be achieved until four or more treatments have been taken in an optimal setting. The data also confirm that 3 mg has superior activity. Patients should therefore be encouraged to try a minimum of 4 doses at 3 mg.
Uprima®, apomorphine sublingual (apo SL) is the first example of a centrally acting drug that was developed to circumvent some of the problems of previously available therapies. In particular, the route of administration and the specific formulation were developed to ensure control and rapidity of onset and to provide a greater separation of the optimal dose range from the compliance limiting side effects that are associated with less sophisticated forms of administration.1−3 Apo SL primarily acts on dopamine D2 receptors in centres of the hypothalamus essential to erection, thereby enhancing the responsiveness to erectogenic stimuli.4 Couples may find this mechanism more attractive, as the pharmacological effect is likely to enhance the erectile response to their own sexual and emotional intimacy, rather than simply replace it with a primarily drug-induced erection. In addition there is information that suggests that dopamine is involved in learned responses and certainly the positive reinforcement of a successful response to sexual activity would aid greatly in the sexual rehabilitation of a couple experiencing the impact of erectile dysfunction (ED).5
It is possible to assess the impact of sequential administrations on the response of patients to apo SL. It is well known, for several drug classes, that several doses are required to achieve an optimal response6 and conversely there are drugs where repeated dosing can lead to pharmacological tolerance and diminution of effect.7 The clinical trials data for apo SL detail the response to such sequential dosing under conditions of similar stimulus, in that the patients and their partners engaged in regular sexual attempts in a familiar environment. The reproducibility of effect with Uprima® has been documented1 and in this analysis the efficacy enhancement with sequential dosing has been examined.
The data used for this analysis are compiled from analyses of the approved 2 and 3 mg doses of apomorphine SL in three blinded, randomised, crossover trials versus placebo. The inclusion and exclusion criteria are fully detailed elsewhere, but represent patients in the ‘real world’ or as presenting to the community physician.1,2 Patients were asked to keep a diary for each tablet taken, to be completed just after intercourse. Their partner concomitantly and independently completed a similar diary. Therefore all data have been compiled from diaries that recorded results by each individual attempt rather than by generalised retrospective patient outcomes. The primary endpoint in all studies was the presence of an ‘erection firm enough for intercourse’ in the view of the patient (and partner). Data from 310 patients were analysed, with 188 patients treated with 2 mg and 122 patients treated with 3 mg of apo SL. Patients were included in this analysis if they made and recorded at least 8 attempts (ie taking the tablet and completing the diary) during the treatment period.
The impact of repeated administration is shown in Figure 1.
The first dose of apo SL was effective in 50% of patients and a greater effect is seen with sequential treatments, reaching a stable rate between treatment 4 and 6. Thereafter, the benefit is maintained with 74% of patients achieving successful erection within the first eight doses of medication. In those patients achieving a response to placebo, there was a similar temporal response to placebo. However the magnitude of the placebo response was markedly less over the same number of doses.
The responses to 2 and 3 mg were qualitatively similar with 4, 5 and 6 treatments being superior to 1. However, as has been documented elsewhere, the absolute number of patients responding to each dose is different.8 In addition, the maximum benefit was achieved with fewer doses of 3 mg Uprima®. Irrespective of the dose, the data show that a reliable response to apo SL will be fully realised after 4 to 6 attempts.
Both 2 and 3 mg doses were well tolerated which further underscores the desirability of persisting with treatment for at least 4 doses.
The clinical benefit of Uprima® in ED treatment is well-documented.1−3,8,9 This analysis demonstrates that the persistence to at least 4 doses will ensure that the patients have a greater opportunity to realise the full potential of the therapy. However, several additional factors may need to be accounted for in order to customise and optimise therapy. For instance, the optimal trial of therapy should be reviewed with the patient in the context of adequate sexual stimulus, appropriate use of the sublingual tablet, or other contributory health factors that may influence the response. Overall, however, it can be concluded that over 70% of patients using at least 4 doses may well expect to achieve success with Uprima®.
Apo SL is known to be rapid in onset of effect (34% of attempts within 10 minutes, 71% of attempts within 20 minutes) with a consistent, predictable response that is seen in men with all degrees of severity (mild, moderate or severe), in all examined underlying aetiologies and in the presence of significant and common co-morbidities (coronary artery disease, hypertension etc). Most importantly, there is also consistent long-term clinical benefit (>90% of attempts being successful over 18 months in established responders1) and a benign side effect profile. The side effect profile is not affected by associated co-morbidities.9
At 2 and 3 mg, apomorphine SL has only modest cardiovascular effects and there do not appear to be clinically significant interactions with widely used antihypertensive agents.9,10 Although there may be slight predictable additive effects with nitrates, the magnitude and the profile of the clinical response should be minimal and, if observed, is substantially smaller than that observed with sildenafil.9,10
The documentation of a progressive improvement with sequential administrations of apomorphine SL has important implications. The data describes the clinical performance of the drug in ‘real life’ use and will be of considerable value in the appropriate counselling of patients.2 Patients are often reluctant to engage in a detailed review of their intimate lives but they must be given good basic instruction on how to achieve an optimal effect. Based on these data the opportunity to realise a benefit from apo SL will increase with the number of doses correctly taken through the sixth dose. The factors influencing this rise in mean benefit are biological (a general or drug specific reinforcement of beneficial learned behaviour) but are not quantifiable at present. Critical to experiencing the potential benefit are the maintenance of safety and the optimisation of chance of success. Users should be given proper instruction in administration (place the tablet under the tongue after a sip of water, allow it to dissolve slowly, for up to 10 minutes, without swallowing it). They should also be offered advice on enjoying adequate physical and emotional sexual stimulation before attempting sexual intercourse. The resumption of a healthy sexual life after a period of disturbed function inherently involves the couple re-learning confidence and technique in the presence of the new drug. The experience of a rapid, natural erection within 20 minutes (the response time of the majority) will guide the couple back to a normal sexual experience after only a few attempts —the present analysis suggests that 4 to 6 doses may be required for optimal effect.
Underpinning the benefit is the fact that apo SL is well-tolerated and safe9 ensuring that the sequential administration of 4 to 6 tablets constitutes a safe and reasonable trial of therapy. In trials with 2 and 3 mg only 6.8% of men reported nausea, 6.8% reported headaches, 4.4% reported dizziness and less than 0.2% reported syncope. The reported nausea is essentially mild, occurs much less frequently than side effects encountered with most widely used medications and tends to resolve with repeated use.9
The present assessment provides additional information for patient guidance. Although many men will respond well to the initial 2 mg dose, it is important not to label those who do not initially respond to the first few doses as ‘non responders’. Some men may well give up after just one or two unsuccessful attempts with oral therapy. However, patients without an initial response should be closely questioned about how they administered the tablet, how many doses they have taken and under what circumstances. Based on this analysis, it is clear that the opportunity for additional benefit can be accrued by repeated, correct administration and/or by increasing the dose to 3 mg. Given the favourable side effect profile9 the routine use of 3 mg in the majority of patients can be encouraged.
Ideally, it should be explained to all patients and partners that the response to any ED therapy will initially be affected because of general stress and performance anxiety, factors that inhibit erectile function. It should also be explained that an improved response to a drug after a period of use is characteristic of many types of therapy with which they are likely to be familiar eg antihypertensive, diabetic and BPH medications. Even a single erection experienced in response to the first few doses is a positive sign that apo SL is a suitable drug for an individual patient. The enhanced effect, observed with Uprima®, over several administrations may be due to learned experience and reductions in stress and performance anxiety, and may possibly even represent a specific benefit of the mechanism of action itself.
Heaton JPW. . Characterising the benefit of apomorphine as an optimised treatment for representative populations with erectile dysfunction. Int J Impot Res 2001 13: Suppl 3 S35–S39.
Von Keitz A. . The management of erectile dysfunction in the community. Int J Impot Res 2001 13: Suppl 3 S45–S51.
Dula E, Bukofzer S, Perdock R, George M. . Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol 2001 39: 558–564.
Giuliano F, Allard J. . Dopamine and sexual function. Int J Impot Res 2001 13: Suppl 3 S18–S28.
Reynolds JN, Hyland BI, Wickens JR. . A cellular mechanism of reward-related learning. Nature 2001 413: 67–70.
Kirby R. . Clinical pharmacology of alpha1-adrenoceptor antagonists. Eur Urol 2001 36: Suppl 1 48–53.
El-Galley R, Rutland H, Talic R, Keane T, Clark H. . Long-term efficacy of sildenafil and tachyphylaxis effect. J Urol 2001 166: 927–931.
Mulhall JP, Bukofzer S, Edmonds AL, George M. . An open label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction. Clin Ther 2001 23: 1260–1271.
Bukofzer S, Livesey N. . Apomorphine safety and tolerability. Int J Impot Res 2001 13: Suppl 3 S40–S44.
Fagan TC, Buttler S, Marbury T, Taylor A, Edmonds A. . Cardiovascular safety of sublingual apomorphine in patients on stable doses of antihypertensive agents and nitrates. Am J Cardiol 2001 88: 760–766.
About this article
Cite this article
Heaton, J., Dean, J. & Sleep, D. Sequential administration enhances the effect of apomorphine SL in men with erectile dysfunction. Int J Impot Res 14, 61–64 (2002). https://doi.org/10.1038/sj.ijir.3900831
- treatment optimisation
- sequential administration
- erectile dysfunction
- apomorphine SL
International Journal of Impotence Research (2020)
International Journal of Impotence Research (2020)
The World Journal of Men's Health (2019)
European Journal of Pharmacology (2019)
Arab Journal of Urology (2013)