GAG layer therapy clinic - a urology nurse consultant's perspective - Carol Edmunds

Interstitial cystitis or bladder pain syndrome (IC/BPS) is a chronic condition characterised by chronic pelvic pain in the absence of a proven urinary tract infection. The symptoms vary on a patient to patient basis but may include pain related to bladder filling, frequency and urgency. IC/BPS may be considered a functional chronic pain disorder affecting the pelvis, rather than a condition specific to the bladder. IC/BPS is a poorly understood bladder condition that is more common in females [1] and probably has a multifactorial cause; it can have a significant impact on lifestyle, work, emotional wellbeing and relationships. As IC/BPS is a diagnosis of exclusion with allodynic symptoms and non-specific diagnostic features without any pathognomonic findings, it is consequently a very difficult condition to diagnose which can take on average up to seven years to diagnose and start treatment; this significantly adds to the condition’s impact on a person.

GAG layer therapy

It has been hypothesised that a defect of the glycosaminoglycan (GAG) layer of the bladder results in IC/BPS. The GAG layer comprises hyaluronic acid, heparin sulphate, chondroitin 4-sulphate, dermatan sulphate and keratin sulphate, and it is thought that this functions as a barrier for the bladder surface. GAG therapy has been used since the 1990s and is widely accepted as a successful treatment option for patients diagnosed with IC/BPS who have had a poor response to other treatment methods.

GAG therapies are also recommended to treat recurrent urinary tract infections, chemical induced cystitis including BCG therapy and radiation induced cystitis [2,3,4] but I am focusing only on patients with IC/BPS in this article.

The treatment pathway

Prior to being referred to the clinic the patient should have been asked to complete a bladder / food diary and, if indicated, eliminate triggering food and drink – these can sometimes be re-introduced once the patient's symptoms are controlled.

The patient will have been assessed on an individual basis and options discussed regarding trigger points, if identified these may include advice on smoking cessation (as smoking and the chemicals in tobacco are known bladder irritants), pelvic floor exercises, and relaxation therapy to assist in lowering stress levels which in some cases can act as a trigger point of a flare in IC/BPS symptoms.

It is important to remember when meeting the patient for the first time that it may have taken a long time for that individual to get to this point and often patients feel that nothing will ever help control their symptoms and give them back quality of life. Consequently extra time may be needed with these patients and I feel this is a vital part of the patient's journey in accepting that bladder instillation therapy can work.

Intravesical hyaluronic acid (HA) is still not available in every hospital to treat IC/BPS which may be as a result of variable response rates. In 2007 Lavazzo et al. concluded that the efficacy of HA remained unproven in controlled and blinded trials [5], although response rates range from 30% to as high as 71% in different studies [6,7].

GAG layer therapy is widely available commercially in different formats (Table 1) but due to lack of awareness or funding is still not widely used in all hospitals. When I first started my instillation clinic back in 2011 there were even fewer hospitals undertaking this service and no widely available recommendations for its schedule of use so I decided to trial a few regimes and see which one seemed to work best for patients. I still use this regime with most of my patients now.

Treatment regime

The regime I use is Cystistat^® 50ml administered once weekly for six weeks then monthly for six months if symptoms have improved. If there is no improvement I will introduce iAluril® (hyaluronic acid with chondroitin sulphate in a pre-filled syringe) as my second-line treatment using the same regime. iAluril^® contains 20 times the concentration of HA compared with Cystistat^®. This format also has the added benefit of the patient being able to self-administer if appropriate and being available on FP10. Hyacyst^® (Sodium Hyaluronate) is also available in a pre-filled syringe format and is available on FP10. If a patient is able to self-administer it means fewer hospital visits which, from a patient perspective, reduces the impact of the treatment on their life [10].

Why do I use the above regime? The answer is simple: it is mostly due to consultant choice with evidence of its efficacy and from a hospital / Clinical Commissioning Group perspective cost-efficiency, especially when compared with long-term oral medication some of which can often be stopped once the treatment has started. The current European Association of Urology (EAU) guidelines, which serve as an ongoing review of current evidence highlights the fact that most studies are uncontrolled and involving small patient numbers in spite of intravesical therapy being in use for around 20 years [11]. Several commercial formulations are available, as summarised in Table 1.

Patients are fully assessed before each instillation to ensure the correct drug is being administered based on symptomatic response, and referred back to the referring consultant if there is no improvement or worsening of symptoms for consideration of other treatment options. Ideally we should see an improvement in the patient’s symptoms before the end of the weekly regime.

With my regime, at the end of the six months the patients are discharged on a SOS basis which gives them the chance to request re-assessment if they feel more treatment is required. I will fully assess these patients prior to any treatment being restarted to ensure this is the correct pathway for the patient and review by the consultant is not indicated.

Intravesical GAG instillation is well tolerated with most side-effects being as a result of the need for urethral catheterisation to administer the drug which may cause urethral or bladder discomfort and a low risk of infection.

Early in 2018, I was able to trial a new way of administering iAluRil^® without the need for catheterisation. Instead of a catheter being inserted to administer iAluRil^®, an adapter, called the iAluadapter^® was fitted to the syringe (Figure 1), which is used to reduce the risk of catheter side-effects. This is only licensed for use with iAluRil^® and is now included as standard in all iAluRil^® packs.Early in 2018, I was able to trial a new way of administering iAluRil^® without the need for catheterisation. Instead of a catheter being inserted to administer iAluRil^®, an adapter, called the iAluadapter^® was fitted to the syringe (Figure 1), which is used to reduce the risk of catheter side-effects. This is only licensed for use with iAluRil^® and is now included as standard in all iAluRil^® packs.

From a personal perspective, I have found the iAluadapter^® easy to use and well tolerated by patients although the patients need to be able to void prior to administration of iAluRil^® using this method as they are required to keep it within their bladder for 30 minutes for maximum effect. Patients sometimes find their pain is worse when the bladder is full and I have found if the patient has not been able to completely empty their bladder prior to the instillation this increases the risk of leakage of the instilled solution. If I do find there is leakage on instillation and I am unable to administer iAluRil^® by using the iAluadapter^® I revert to inserting a catheter to empty the bladder and then administer iAluRil^®, which is not a common occurrence. The use of the iAluadapter^® removed the fear of catheterisation in some patients and, as with other GAG-layer therapies, can allow for some self-administration regimes, but we need further studies to identify better patient selection and use of such therapies earlier in the treatment pathway.

Take home message

• Bladder pain syndrome / interstitial cystitis is a difficult condition to treat.
• Intravesical GAG replacement therapies may be used as an alternative to long-term drug therapy.
• Intravesical GAG layer therapy is easy to administer and is well-tolerated.
• There is a wealth of clinical experience available but a lack of high quality research evidence to support its use; more clinical trials are required to enable standardisation of treatment regimes.

References

1. Clemens JQ , Link CL, Eggers PW, et al. Prevalence of painful bladder symptoms and effect on quality of life in black, Hispanic and white men and women J Urol 2007;177(13):90-4.
2. Damiano R, Quarto G, Bava I, et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. Eur Urol 2011;59(4):645-51.
3. Imperatore V, Creta M, et al. Intravesical instillation of sodium hyaluronate–chondroitin sulfate in patients with Bacillus Calmette-Guérin-induced chemical cystitis unresponsive to conventional therapies: Preliminary experience with 1 year follow-up. Eur Urol Suppl 2014;13:e466.
4. Gacci M, et al. Bladder instillation therapy with hyaluronic acid and chondroitin sulfate improves symptoms of post radiation cystitis: prospective pilot study. Clin Genitourinary Cancer 2016;14(5):444-9.
5. Lavazzo C, Athanasiou S, Pitsouni E, Falagas ME. Hyaluronic acid: an effective alternative treatment of interstitial cystitis, recurrent urinary tract infections, and hemorrhagic cystitis? Eur Urol 2007;51(6):1534-40.
6. Morales A, Emerson L, Nickel JC, et al. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol 1996;156:45-8.
7. Cervigni M, Natale F, Nasta L, et al. A combined intravesical therapy with Hyaluronic acid and Chondroitin for refractory painful bladder syndrome/interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 2008;19(7):943-7.
8. Kallestrup EB, Jorgensen SS, Nording J, et al. Treatment of interstitial cystitis with cystistat an hyaluronic acid product. Scand J Urol Nephrol 2005;39:143-7.
9. Nickel JC, Egerdie B, Downey J, et al. A real life multicenter clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis. BJU Int 2009;103:56-60.
10. Willard K. Poster 27: A patient centred approach in the management of painful bladder syndrome. 24th UKCS Annual Scientific Meeting 2017.
11. Engeler D, Baranowski AP, Borovicka J, et al. EAU Guidelines on Chronic Pelvic Pain. 2018.

Carol Edmunds,
Nurse Consultant Urology, North West Anglia NHS Foundation Trust.
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Declaration of competing interests:

The author has been reimbursed by Aspire Pharma, the manufacturer of iAluRil® to attend a conference to discuss GAG layer therapy and her hospital was a trial centre for the new iAluadapter^®.

Figure 1: iAluril^® with iAluadapter^®.

Hot quote: "With my regime, at the end of the six months the patients are discharged on a SOS basis which gives them the chance to request re-assessment if they feel more treatment is required"