¹The Pain Management Centre, University College London Hospitals NHS Trust, The National Hospital for Neurology and Neurosurgery, London, UK

²St Peter's Hospital, The Institute of Urology and Nephrology, University College London Hospitals NHS Trust, The Middlesex Hospital, London, UK

³University College London, London, UK

⁴Department of Vascular Surgery, University College London Hospitals NHS Trust, Middlesex Hospital, London, UK

Correspondence to: L M Harding, The Pain Management Centre, University College London Hospitals NHS Trust, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. E-mail: louise.harding@uclh.org

Patients identified from hospital records as using alprostadil injections for erectile dysfunction were invited to take part in this open crossover study. On alternate weeks eight patients were given intracavernosal needle injections and transdermal needle-free injection of alprostadil in a randomized order. Efficacy of injection and associated pain were assessed and compared for the two methods. Pain produced during injection was significantly greater with the needle-free system than with the needle-tipped injection whilst efficacy was significantly less. Bruising was reported in all except one patient following needle-free injection only. Patient ratings of the needle-free injector were significantly lower than ratings for needle-tipped alprostadil delivery and when asked to express a preference, every patient chose the needle-tipped injection over the needle-free device.

International Journal of Impotence Research (2002) 14, 498-501. doi:10.1038/sj.ijir.3900916

alprostadil; pain; needle-free; erectile dysfunction

Introduction

Sildenafil is now recommended as first line treatment for erectile dysfunction (ED).^1,2 For the many patients who are contraindicated, cannot tolerate, or gain insufficient response from this drug, intracavernosal (IC) alprostadil injections are typically the next treatment offered. When the right dose is found, IC alprostadil is effective in producing an erection adequate for intercourse in 70-90% of men.^4,5,6,7,8 However, many patients find the idea of penile injection unacceptable. In addition, side effects, including bleeding on injection, bruising, penile pain and fibrosis,^5,8 contribute to patient dissatisfaction. Intra-urethral alprostadil delivery is a putative alternative, although the higher doses of drug needed to elicit a response results in lower tolerability amongst patients and this route is less efficacious than direct injection into the erectile bodies.⁶ The introduction of a new delivery method for intracavernosal alprostadil which can overcome at least some of these problems would be of benefit to a significant proportion of ED patients.

Needle-free injectors propel drugs through tissues using pressurized (liquid) CO₂ as the driving force and have been used in a number of applications including administration of local anaesthetic,^9,10 insulin,^11,12 intramuscular immunization^13,14 and interferon.¹⁵ These studies have shown that needle-free drug delivery can be as effective and produce less pain and anxiety than traditional needle injection. To be effective in ED, the injector must be able to propel the drug across the dense tunica albuginea into the corpora carvonosa. As far as we are aware, no evidence of this has been reported in man, although it has been demonstrated in rats.¹⁶ If the qualities of needle-free injectors shown in previous applications are maintained in penile administration, this method may prove to be a viable alternative to needle-tipped IC drug delivery. In the following study we assess the pain, efficacy and patient preference of penile alprostadil administration with a needle-free injector.

Methods

Patients with ED of mixed aetiologies identified as having used alprostadil injections in the previous 2 y were invited to take part in the study. Eight patients took part; the median age was 56 (range 39-76). Mean duration of intracavernosal alprostadil injection use was 2.7 y (range 1 month to 5.5 y) and mean weekly frequency of use was 1.4 (range 1-2). One patient with a spinal cord injury had no sensory function below L4 and consequently his data were not used in the pain assessment analysis.

Patients were randomized to order of treatment using unmarked, sealed envelopes. All injections were given by the same physician. Alprostadil (Viridal DuoÔ, Schwarz Pharma) was used for both injection systems. An individualized dosing strategy was used where all patients were given the same dose of alprostadil that they normally used. Doses were 20 µg (n=7) and 15 µg (n=1). The drug was administered in 0.5 ml saline. Patients normally used an injection volume of 1 ml, but as 0.5 ml was the maximum capacity of the needle-free injector, 0.5 ml was used for both methods. A 30-gauge needle was used in needle-tipped delivery and the J-tip needle-free injector (National Medical Products), Figure 1, was used for the needle-free group. The duration between the two injections was one week.

Injections were given on the opposite side of the penis to that most recently injected. The injection area was wiped with alcohol and the penis bent to stretch the loose skin and bring the corpus cavernosum closer to the surface. After injection, the penis was rubbed gently for approximately 30 s to aid spreading of the drug throughout the corpora. The patient was asked to rate both pain produced during injection and pain present in the 5 min following injection, on a 0-10 ordinal scale (with 0 corresponding to no pain and 10 corresponding to worst pain imaginable). Following injection the physician left the room, returning at 5 min intervals to assess the stage the erection had reached. Time to first response was noted by the physician and the maximum response elicited was rated by both clinician and patient on the four-point scale (where 0=no erection, 1=minimum response, 2=full enlargement and 4=full erection adequate for intercourse). Observation time was for 40 min after injection or, if sooner, until maximum response was seen. After the observation period, patients rated the injection method, taking into consideration pain, speed of response and efficacy on a 0-10 ordinal scale (where 0 corresponds to 'very poor' and 10 corresponds to 'excellent'). A 7 day patient diary recording pain at 1, 2, 4 and 24 h after injection and any other problems/side effects noted over the subsequent week was completed following each injection. Patients were followed up one week after the second injection and asked to state, on reflection, which of the two injection, methods they preferred.

Non-parametric statistics were applied to the data. Treatments were compared using Wilcoxon matched pairs signed rank two-tailed test. P-values< 0.05 were considered statistically significant.

Results

Pain ratings, both on and following injection, are shown in Figure 2. On injection, pain produced by the needlefree injector was significantly greater than the needle-tipped injection (P=0.016). Individually, all patients reported more pain with the needle-free system than with the needle-tipped method. Median pain score on injection was 1 (range 0-2) for needle-tipped, compared with 5 (range 1-8) for the needle-free injector. Pain produced by the two systems was not statistically different at any of the assessed time points after injection (P>0.05).

The subjective patient rated response showed the needle-free system to be significantly less efficacious than needle-tipped delivery (P=0.016; Figure 3a). The difference between the two injection methods, however, did not reach significance with the objective response rating of the examining doctor (P=0.063; Figure 3b). Five patients developed at least full enlargement with needle-tipped delivery whereas none reached this response category with the needle-free system (both objective and subjective assessment). Response was monitored for a maximum of 40 min following injection. When questioned retrospectively, no patient reported any improvement in quality of erection after this time with either of the injection methods. The time to first response was not significantly different between the two groups (P=0.313). The median first response time was 5 min (range 5-25) for needle-tipped, but 10 min (range 10-20) for needle-free drug delivery.

A comparison of patient ratings for the two delivery systems is shown in Figure 4. The traditional needle delivery was rated significantly higher than the new needle-free method (P=0.0078). Median rating for the needle-free system was 0 (range 0-3), whereas median rating for needle-tipped delivery was 8 (range 1-8). It should be noted that these ratings were given before notable side effects had developed, or pain in the hours post-injection was experienced.

Seven patients reported bruising following needle-free delivery. This bruising, which occurred between visits and consequently was not examined by the physician, was reported as ranging in size from approximately 1 cm² (described by a patient as the size of a British one penny piece; one patient) to the entire length of the shaft (two patients). Median duration of bruising was 5 days (range 3-7 days). No bruising was observed following needle-tipped delivery.

When asked to express a preference, one week after the last injection, all eight patients chose the needle-tipped injection method.

Discussion

The needle-free injector produced more pain than needle-tipped delivery, was less effective and produced bruising. The pain evoked was unexpected as needle-free injection is generally associated with less pain than needle-tipped syringes.^10,15 Without a saline control it is difficult to state whether the pain was due to tissue trauma alone or due to the combined effect of trauma with the exogenous prostaglandin. Slow alprostadil i.c. injection is thought to be less painful than fast injection.¹⁷ The high-pressure system is extremely fast, injecting drug in a fraction of a second. If speed is a key factor in causing pain then, even with modifications, it is unlikely that high-pressure injection will be a suitable instrument for erectile dysfunction treatment.

Seven patients reported bruising following needle-free injection which was repeatedly described as distressing and unacceptable. Increased incidence of bruising has been shown previously with pressure injections, but bruising did not affect patient preference.¹⁸ This suggests, perhaps unsurprisingly, that acceptance of bruising is strongly dependent on the location of the bruise!

The lack of efficacy of the needle-free method suggests that insufficient drug is reaching the corpora carvonosa. Most patients developed a discrete localized swelling around the injection site following needle-free injection (rated as a 'minimal response' by the physician but as 'no response' by the patient, explaining the discrepancy between patient and doctor response ratings). With higher doses and adjustments to the injection device to allow increased drug volumes an effective dose may be found. However, the side effects of pain and bruising would still have to be addressed for the method to be acceptable to most patients. Interestingly, some patients did not obtain a full erection with needle-tipped injection using the dose of alprostadil they successfully use at home. This suggests the importance of drug volume and role of psychosexual input and environment in evoking a response.

Although all patients in this study preferred the traditional injection method it is worth remembering that the study sample was not truly representative of all patients with ED as only patients comfortable with injecting themselves were included. If a true cross section were taken we would expect to see both higher pain scores for needle-tipped delivery and a lower overall rating for this method.

The small sample size of this study is also acknowledged; the original intention of the study was to have a larger patient population. From the observations seen in just eight patients however, we felt it both unnecessary and unethical to increase the sample size. Even with a small sample size this study clearly shows that, in its present form, the J-tip high-pressure needle-free injection systems is not a viable device for penile alprostadil administration.

1 Leungwattanakij S, Flynn V Jr, Hellstrom WJ. Intracavernosal injection and intraurethral therapy for erectile dysfunction. Urol Clin N Am 2001; 28: 343-354.

2 Vitezic D. A risk-benefit assessment of sildenafil in the treatment of erectile dysfunction. Drug Saf 2001; 24: 255-265.

3 Pryer JL, Redman B. New therapies and delivery mechanisms for treatment of erectile dysfunction. Int J Impot Res 2000; 12: S158-S162.

4 Bodner DR, Leffler B, Frost F. The role of intracavernous injection of vasoactive medications for the restoration of erection in spinal cord injured males: a three year follow up. Paraplegia 1992; 30: 118-120.

5 Purvis K, Egdetveit I, Christiansen E. Intracavernosal therapy for erectile failure¾impact of treatment and reasons for drop-out and dissatisfaction. Int J Impot Res 2000; 12: 131.

6 Shabsigh R et al. Intracavernous alprostadil alfadex is more efficacious, better tolerated, and preferred over intraurethral alprostadil plus optional actis: a comparative, randomized, crossover, multicenter study. Urology 2000; 55: 109-113. Article MEDLINE

7 Baniel J, Israilov S, Segenreich E, Livne PM. Comparative evaluation of treatments for erectile dysfunction in patients with prostate cancer after radical retropubic prostatectomy. BJU Int 2001; 88: 58-62.

8 Brock G, Tu LM, Linet OI. Return of spontaneous erection during long-term intracavernosal alprostadil (Caverject) treatment. Urology 2001; 57: 536-541. Article MEDLINE

9 Saravia ME, Bush JP. The needless syringe: efficacy of anesthesia and patient preference in child dental patients. J Clin Pediatr Dent 1991; 15: 109-112.

10 Cooper JA, Bromley LM, Baranowski AP, Barker SGE. Evaluation of a needle-free injection system for local anaesthesia prior to venous cannulation. Anaesthesia 2000; 55: 247-250.

11 Danowski TS, Sunder JH. Jet injection of insulin during self monitoring of blood glucose. Diabetes Care 1978; 1: 27-33.

12 Katoulis EC et al. Efficacy of a new needless insulin delivery system monitoring of blood glucose fluctuations and free insulin levels. Int J Artif Organs 1989; 12: 333-338.

13 Davis HL et al. Direct gene transfer in skeletal muscle: plasmid DNA-based immunization against the hepatitis B virus surface antigen. Vaccine 1994; 12: 1503-1509. MEDLINE

14 Gramzinski RA et al. Immune responses to a hepatitis B DNA vaccine in Aotus monkeys: comparison of vaccine formulation, route, and method of administration. Mol Med 1998; 4: 109-118.

15 Brodell RT, Bredle DL. The treatment of palmar and plantar warts using natural alpha interferon and a needless injector. Dermatol Surg 1995; 21: 210-212.

16 Seyam RM et al. Evaluation of a no-needle penile injector: a preliminary study evaluating tissue penetration and its hemodynamic consequences in the rat. Urology 1997; 50: 994-998.

17 Gheorghiu D, Godschalk M, Gheorghiu S, Mulligan T. Slow injection of prostaglandin E1 decreases associated penile pain. Urology 1996; 47: 903-904.

18 Verrips GH et al. Psychological responses to the needle-free Medi-Jector or the multidose. Disetronic injection pen in human growth hormone therapy. Acta Paediatr 1998; 87: 154-158.

Figure 1 The J-tip needle free drug delivery system. Drug is loaded into the transporter unit (a) which, after removal of the protective cap (i), is then transferred to the barrel of the injection device (b). Activating the trigger (iii) releases the liquid CO₂ (iv) which activates the plunger (ii) expelling the drug from the injector.

Figure 2 Pain evoked on injection and 24 hrs following injection are shown for needle-tipped intracarvenosal alprostadil delivery (a) and high pressure injector needlefree delivery (b) (n=7).

Figure 3 Quality of erection produced by needle-tipped injection and needlefree injection as rated by patient (a) and physician (b) (n=8). Data shown are medians and interquartile ranges, *P<0.05, ns=no significant difference.

Figure 4 Overall rating of the two delivery methods taking into account pain, efficacy and time to response (n=8). Data shown are medians and interquartile ranges, **P<0.01.